Substituted xanthines and methods of use thereof

ABSTRACT

Compounds, compositions and methods are described for inhibiting the TRPC5 ion channel and disorders related to TRPC5.

CLAIM OF PRIORITY

This application is a Continuation of, and claims priority to, U.S.patent application Ser. No. 15/968,941, filed May 2, 2018 (allowed),which is a Continuation of, and claims priority to, U.S. patentapplication Ser. No. 15/622,838, filed Jun. 14, 2017 (U.S. Pat. No.9,969,736); which is a Continuation of, and claims priority to, U.S.patent application Ser. No. 15/137,327, filed Apr. 25, 2016; which is aContinuation of, and claims priority to, U.S. patent application Ser.No. 14/210,781, filed Mar. 14, 2014, (U.S. Pat. No. 9,359,359); whichclaims priority to U.S. Provisional Application No. 61/789,724, filedMar. 15, 2013, the contents of which are incorporated herein byreference in its entirety.

BACKGROUND

A variety of ion channel proteins exist to mediate ion flux acrosscellular membranes. The proper expression and function of ion channelproteins is essential for the maintenance of cell function,intracellular communication, and the like. Numerous diseases are theresult of misregulation of membrane potential or aberrant calciumhandling. Given the central importance of ion channels in modulatingmembrane potential and ion flux in cells, identification of agents thatcan promote or inhibit particular ion channels are of great interest asresearch tools and as possible therapeutic agents.

SUMMARY OF THE INVENTION

The present invention provides methods of treating a TRPC5 mediateddisorder in a subject, comprising administering to the subject acompound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein constituentmembers are provided herein.

The present invention further provides compounds of Formula I(a):

or a pharmaceutically acceptable salt thereof, wherein constituentmembers are provided herein.

The present invention further provides compounds of Formula II:

or a pharmaceutically acceptable salt thereof, wherein constituentmembers are provided herein.

The present invention further provides compounds of Formula III:

or a pharmaceutically acceptable salt thereof, wherein constituentmembers are provided herein.

The present invention further provides compositions comprising acompound of Formula I(a), II or III, and a pharmaceutically acceptablecarrier.

The present invention further provides methods of treating a TRPC5mediated disorder in a subject, e.g. a human, comprising administeringto the subject a compound or composition of a compound of Formula I(a),II or Formula III, or a pharmaceutically acceptable salt thereof.

The present invention provides methods, compounds and compositions fortreating conditions such as a neuropsychiatric disorder, aneurodegenerative disorder, nephropathy, and seizure disorder bymodulating the activity of the transient receptor potential cationchannel subfamily C, member 5 (TRPC5), which can exist in homomultimericform as well as heteromultimeric form with other ion channels such asTRPC1 or TRPC3 (i.e., TRPC5-TRPC1 and TRPC1-TRPC3-TRPC5). The compoundsdescribed herein modulate the function of TRPC5 by inhibiting aTRPC5-mediated ion flux or by inhibiting the inward current, the outwardcurrent, or both currents mediated by TRPC5. The inhibition of aparticular current is the ability to inhibit or reduce such current(e.g., inward and/or outward) in an in vitro or an in vivo assay. Theactivation of a particular current is the ability to activate orincrease such current (e.g., inward and/or outward) in an in vitro or anin vivo assay.

In one aspect, the invention relates to a method for treating acondition for which reduced TRPC5 activity can reduce the severity ofthe condition, by administering a TRPC5 antagonist, such as a compoundas described herein that inhibits TRPC5-mediated current and/orTRPC5-mediated ion flux. Described herein are compounds, which are TRPC5antagonists that have a measured IC₅₀ for inhibition of TRPC5 of 10nanomolar or less. In certain embodiments, the compounds describedherein, which are TRPC5 antagonists inhibit one or both of inward andoutward TRPC5-mediated currents with an IC₅₀ 10 nanomolar or less. Incertain embodiments, the compounds described herein inhibit at least 95%of TRPC5-mediated current or TRPC5-mediated ion flux when administeredat 1 micromolar or less.

In another aspect, the compounds described herein, which are TRPC5antagonists can be used to inhibit a function of TRPC5, for example aTRPC5-mediated current and/or a TRPC5-mediated ion flux. In someembodiments, the compounds described herein can be used to inhibit aTRPC5 mediated current in vitro, for example in cells in culture. Inother embodiments, the compounds described herein can be used to inhibita TRPC5 mediated current in vivo. In certain embodiments, the compoundsdescribed herein inhibit both an inward and an outward TRPC5-mediatedcurrent.

Another aspect of the invention features a pharmaceutical preparationsuitable for use in a human patient, or for veterinary use, comprisingan effective amount of a compound described herein (or a salt thereof,or a solvate, hydrate, oxidative metabolite or prodrug of the compoundor its salt), and one or more pharmaceutically acceptable excipients.The invention further contemplates the use of the compounds describedherein in the manufacture of a medicament or pharmaceutical preparationto treat or reduce the symptoms of any of the diseases or conditionsprovided in the specification. The compounds described herein can beused for treating a particular disease or condition can be formulatedfor administration via a route appropriate for the particular disease orcondition.

The compounds described herein can be administered alone or incombination with another therapeutic agent. For instance, the compoundsdescribed herein can be administered conjointly with one or more of ananti-inflammatory agent, anti-acne agent, anti-wrinkle agent,anti-scarring agent, anti-psoriatic agent, anti-proliferative agent,anti-fungal agent, anti-viral agent, anti-septic agent, anti-migraineagent, keratolytic agent, or a hair growth inhibitor.

The compounds described herein can be administered topically, orally,transdermally, rectally, vaginally, parentally, intranasally,intrapulmonary, intraocularly, intravenously, intramuscularly,intraarterially, intrathecally, intracapsularly, intraorbitally,intracardiacly, intradermally, intraperitoneally, transtracheally,subcutaneously, subcuticularly, intraarticularly, subcapsularly,subarachnoidly, intraspinally, intrasternally, sublingually, or byinhalation.

In some embodiments, the compounds described herein can be administeredtopically.

In some embodiments, the compounds described herein can be administeredorally.

In some embodiments, the compounds described herein can be administeredparentally.

DETAILED DESCRIPTION OF THE INVENTION

Cation channels such as TRPC5 modulate the flux of calcium and sodiumions across cellular membranes. Sodium and calcium influx leads to adepolarization of the cell. This increases the probability thatvoltage-gated ion channels will reach the threshold required foractivation. As a result, activation of non-selective cation channels canincrease electrical excitability and increase the frequency ofvoltage-dependent events. Voltage-dependent events include, but are notlimited to, neuronal action potentials, cardiac action potentials,smooth muscle contraction, cardiac muscle contraction, and skeletalmuscle contraction.

Calcium influx caused by the activation of non-selective cation channelssuch as TRPC5 also alters the intracellular free calcium concentration.Calcium is a ubiquitous second messenger molecule within the cell andthe alterations in intracellular calcium levels have profound effects onsignal transduction and gene expression. Thus, activation ofnon-selective cation channels such as TRPC5 can lead to changes in geneexpression and cellular phenotype. Gene expression events include, butare not limited to, production of mRNAs encoding cell surface receptors,ion channels, and kinases. These changes in gene expression can lead tohyperexcitability in that cell.

Transient receptor potential (TRP) homomeric TRPC5 ion channels aresignal transduction gated, Ca²⁺-permeable channels predominantlyexpressed in the neurons. TRPC5 forms homomultimeric structures such astetramers (i.e., TRPC5 homomultimers) and heteromultimeric structuressuch as tetramers (i.e., TRPC5-TRPC1 heteromultimers). Unless expresslystated otherwise, when the term TRPC5 is used herein, for example, whenidentifying a modulator of TRPC5 such as a TRPC5 antagonist, the termTRPC5 is used generically so as to include either or both of a TRPC5homomultimer or a heteromultimer (e.g., TRPC5-TPRC1 or TRPC5-TRPC4heteromultimer). Examples of TRPC5 in the literature include thefollowing: Nature. 2008 Jan. 3; 451 (7174):69-72; Mol Pharmacol. 2008January; 73 (1):42-9; J Biol Chem. 2007 Nov. 16; 282 (46):33868-78;Biochem Biophys Res Commun. 2008 Jan. 11; 365 (2):239-45; J Biol Chem.2006 Nov. 3; 281 (44):33487-96; Eur J Pharmacol. 2005 Mar. 14; 510(3):217-22; J Biol Chem. 2006 Feb. 24; 281 (8):4977-82; Biochem SocTrans. 2007 February; 35 (Pt 1):101-4; Handb Exp Pharmacol. 2007;(179):109-23; J Biol Chem. 2005 Mar. 25; 280 (12):10997-1006; J Physiol.2006 Jan. 15; 570 (Pt 2):219-35; and Nat Neurosci. (2003) 6: 837-45.

Modulating the function of TRPC5 proteins provides a means of modulatingcalcium homeostasis, sodium homeostasis, membrane polarization, and/orintracellular calcium levels, and compounds that can modulate TRPC5function are useful in many aspects, including, but not limited to,maintaining calcium homeostasis, modulating intracellular calciumlevels, modulating membrane polarization, and treating or preventingdiseases, disorders, or conditions associated with calcium and/or sodiumhomeostasis or dyshomeostasis.

In one aspect, the invention provides methods of treating a TRPC5mediated disorder in a subject comprising administering to the subject acompound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which isoptionally substituted with 1-4 R⁵;

R² is C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ haloalkyl, halo, C₁-C₆ haloalkoxy, hydroxyl, C₁-C₆ alkoxy, C₃-C₇cycloalkyloxy, C₆-C₁₀ aryl, C₆-C₁₀ aryloxy, C₇-C₁₆ arylalkoxy, amino,C₁-C₆ akylamino, C₂-C₁₂ dialkylamino, —S—, —S—C₁-C₆ alkyl, —S(O)—,—S(O)₂—, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl,amido, urea, sulfonylurea, acyl, nitro, cyano, wherein each of C₁-C₆alkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, hydroxyl, C₁-C₆ alkoxy, C₃-C₇ cycloalkyloxy, C₆-C₁₀aryl, C₆-C₁₀ aryloxy, C₇-C₁₆ arylalkoxy, amino, C₁-C₆ akylamino, C₂-C₁₂dialkylamino, —S—, —S—C₁-C₆ alkyl, —S(O)—, —S(O)₂—, heterocycloalkyl,heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea,acyl, is optionally substituted with 1-3 R⁶;

R³ is C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₂-C₆ hydroxyalkyl, or C₁-C₆ alkoxy, each of which isoptionally substituted with 1-4 R⁷;

R⁴ is C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl,each of which is optionally substituted with 1-4 R⁸;

R⁵, R⁶, R⁷, and R⁸ are each independently C₁-C₆ alkyl, C₁-C₆heteroalkyl, halo, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxyl, C₁-C₆alkoxy, amino, C₁-C₆ alkylamino, C₂-C₁₂ dialkylamino, cyano, nitro,amido, C₁-C₆ alkylamido, C₂-C₁₂ dialkylamido, —S—, —S(O)₂—, —C(O)O—,—C(O)—, —C(O)O—C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl,heterocycloalkyl, or heteroaryl, wherein each of C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxyl, C₁-C₆ alkoxy,amino, C₁-C₆ alkylamino, C₂-C₁₂ dialkylamino, amido, C₁-C₆ alkylamido,C₂-C₁₂ dialkylamido, —S—, —S(O)₂—, —C(O)O—, —C(O)—, —C(O)O—C₁-C₆ alkyl,C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, heterocycloalkyl, or heteroaryl isoptionally substituted with 1-3 R⁹; and

each R⁹ is independently C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, heterocycloalkyl, C₆-C₁₀ aryl, heteroaryl,C₄-C₁₀ cycloalkylalkyl, heterocycloalkyl-C₁-C₆ alkyl, C₇-C₁₆ arylalkyl,heteroaryl-C₁-C₆ alkyl, halo, hydroxyl, C₁-C₆ alkoxy, C₆-C₁₀ aryloxy,C₇-C₁₆ arylalkoxy, C₂-C₈ alkoxyalkoxyl, amino, C₁-C₆ akylamino, C₂-C₁₂dialkylamino, C₁-C₆ akyl-amino-C₁-C₆ akyl, C₁-C₆ akyl-amino-C₂-C₁₂dialkyl, —S—, —S—C₁-C₆ alkyl, —S(O)₂—C₁-C₆ alkyl, sulfonamidyl, amido,urea, sulfonylurea, acyl, —C(O)—C₆-C₁₀ aryl, —NHC(O)—C₆-C₁₀ aryl,—C(O)NH—C₆-C₁₀ aryl, —C(O)OH, —C(O)O—C₁-C₆ alkyl, —C(O)—C₁-C₆ alkylacyl, nitro, or cyano; to thereby treat the subject.

In some embodiments, the TRPC5 mediated disorder is selected from thegroup consisting of: a neuropsychiatric disorder, a neurodegenerativedisorder, nephropathy, and seizure disorder.

In some embodiments, R¹ is C₁-C₆ alkyl.

In some embodiments, R¹ is C₁-C₆ alkyl and R⁵ is independently C₆-C₁₀aryl or heteroaryl.

In some embodiments, R² is C₆-C₁₀ aryl, C₆-C₁₀ aryloxy or heteroaryloxy.

In some embodiments, R² is C₆-C₁₀ aryloxy.

In some embodiments, R² is C₁-C₆ alkoxy.

In some embodiments, R² is C₁-C₆ alkyl.

In some embodiments, R² is or C₁-C₆ akylamino.

In some embodiments, R² is —S(O)— or —S(O)₂—.

In some embodiments, R³ is C₁-C₆ alkyl, C₂-C₆ hydroxyalkyl, or C₁-C₆alkoxy.

In some embodiments, R³ is C₂-C₆ hydroxyalkyl, e.g., hydroxypropyl.

In some embodiments, R³ is hydroxypropyl.

In some embodiments, R⁴ is C₁-C₆ alkyl.

In some embodiments, R⁵ is independently C₆-C₁₀ aryl, heteroaryl, C₃-C₇cycloalkyl, or heterocycloalkyl.

In some embodiments, R⁵ is phenyl, pyridyl, thiazolyl, pyrimidinyl, oroxazolyl.

In some embodiments, R⁵ is phenyl.

In some embodiments, R⁵ is pyridyl.

In some embodiments, R⁵ is thiazolyl.

In some embodiments, R⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy,halo, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or heterocycloalkyl.

In some embodiments, R² is C₆-C₁₀ aryl or C₆-C₁₀ aryloxy, and R⁶ isindependently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ or haloalkoxy.

In some embodiments, R² is C₆-C₁₀ aryloxy and R⁶ is independently C₁-C₆haloalkyl or C₁-C₆ or haloalkoxy.

In some embodiments, R² is C₆-C₁₀ aryloxy and R⁶ is —CF₃ or —OCF₃.

In another aspect, the invention provides compounds of Formula I(a):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which isoptionally substituted with 1-4 R⁵;

R² is C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ haloalkyl, halo, C₁-C₆ haloalkoxy, hydroxyl, C₁-C₆ alkoxy, C₃-C₇cycloalkyloxy, C₆-C₁₀ aryl, C₆-C₁₀ aryloxy, C₇-C₁₆ arylalkoxy, amino,C₁-C₆ akylamino, C₂-C₁₂ dialkylamino, —S—, —S—C₁-C₆ alkyl, —S(O)—,—S(O)₂—, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl,amido, urea, sulfonylurea, acyl, nitro, cyano, wherein each of C₁-C₆alkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, hydroxyl, C₁-C₆ alkoxy, C₃-C₇ cycloalkyloxy, C₆-C₁₀aryl, C₆-C₁₀ aryloxy, C₇-C₁₆ arylalkoxy, amino, C₁-C₆ akylamino, C₂-C₁₂dialkylamino, —S—, —S—C₁-C₆ alkyl, —S(O)—, —S(O)₂—, heterocycloalkyl,heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea,acyl, is optionally substituted with 1-3 R⁶;

R³ is C₂-C₆ hydroxyalkyl or C₁-C₆ heteroalkyl;

R⁴ is C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl,each of which is optionally substituted with 1-4 R⁸;

R⁵, R⁶, and R⁸ are each independently C₁-C₆ alkyl, C₁-C₆ heteroalkyl,halo, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxyl, C₁-C₆ alkoxy, amino,C₁-C₆ alkylamino, C₂-C₁₂ dialkylamino, cyano, nitro, amido, C₁-C₆alkylamido, C₂-C₁₂ dialkylamido, —S—, —S(O)₂—, —C(O)O—, —C(O)—,—C(O)O—C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, heterocycloalkyl, orheteroaryl, each of C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, hydroxyl, C₁-C₆ alkoxy, amino, C₁-C₆ alkylamino,C₂-C₁₂ dialkylamino, amido, C₁-C₆ alkylamido, C₂-C₁₂ dialkylamido, —S—,—S(O)₂—, —C(O)O—, —C(O)—, —C(O)O—C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₆-C₁₀aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3R⁹; and

each R⁹ is independently C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, heterocycloalkyl, C₆-C₁₀ aryl, heteroaryl,C₄-C₁₀ cycloalkylalkyl, heterocycloalkyl-C₁-C₆ alkyl, C₇-C₁₆ arylalkyl,heteroaryl-C₁-C₆ alkyl, halo, hydroxyl, C₁-C₆ alkoxy, C₆-C₁₀ aryloxy,C₇-C₁₆ arylalkoxy, C₂-C₈ alkoxyalkoxyl, amino, C₁-C₆ akylamino, C₂-C₁₂dialkylamino, C₁-C₆ akyl-amino-C₁-C₆ akyl, C₁-C₆ akyl-amino-C₂-C₁₂dialkyl, —S—, —S—C₁-C₆ alkyl, —S(O)₂—C₁-C₆ alkyl, sulfonamidyl, amido,urea, sulfonylurea, acyl, —C(O)—C₆-C₁₀ aryl, —NHC(O)—C₆-C₁₀ aryl,—C(O)NH—C₆-C₁₀ aryl, —C(O)OH, —C(O)O—C₁-C₆ alkyl, —C(O)—C₁-C₆ alkylacyl, nitro, or cyano.

In some embodiments, R¹ is C₁-C₆ alkyl and R⁵ is phenyl, pyridyl,thiazolyl, pyrimidinyl, or oxazolyl, e.g., phenyl, pyridiyl, orthiazolyl.

In some embodiments, R² is C₆-C₁₀ aryl or C₆-C₁₀ aryloxy, and R⁶ isindependently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ or haloalkoxy.

In some embodiments, R³ is C₂-C₆ hydroxyalkyl, e.g., hydroxypropyl.

In another aspect, the invention provides compounds of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is phenyl, thiazolyl, pyrimidinyl, or oxazolyl;

R² is C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ haloalkyl, halo, C₁-C₆ haloalkoxy, hydroxyl, C₁-C₆ alkoxy, C₃-C₇cycloalkyloxy, C₆-C₁₀ aryl, C₆-C₁₀ aryloxy, C₇-C₁₆ arylalkoxy, amino,C₁-C₆ akylamino, C₂-C₁₂ dialkylamino, —S—, —S—C₁-C₆ alkyl, —S(O)—,—S(O)₂—, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl,amido, urea, sulfonylurea, acyl, nitro, cyano, wherein each of C₁-C₆alkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, hydroxyl, C₁-C₆ alkoxy, C₃-C₇ cycloalkyloxy, C₆-C₁₀aryl, C₆-C₁₀ aryloxy, C₇-C₁₆ arylalkoxy, amino, C₁-C₆ akylamino, C₂-C₁₂dialkylamino, —S—, —S—C₁-C₆ alkyl, —S(O)—, —S(O)₂—, heterocycloalkyl,heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea,acyl, is optionally substituted with 1-3 R⁶;

R³ is C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₂-C₆ hydroxyalkyl, or C₁-C₆ alkoxy, each of which is optionallysubstituted with 1-4 R⁷;

R⁴ is C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl,each of which is optionally substituted with 1-4 R⁸;

R⁶, R⁷, and R⁸ are each independently C₁-C₆ alkyl, C₁-C₆ heteroalkyl,halo, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxyl, C₁-C₆ alkoxy, amino,C₁-C₆ alkylamino, C₂-C₁₂ dialkylamino, cyano, nitro, amido, C₁-C₆alkylamido, C₂-C₁₂ dialkylamido, —S—, —S(O)₂—, —C(O)O—, —C(O)—,—C(O)O—C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, heterocycloalkyl, orheteroaryl, wherein each of C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, hydroxyl, C₁-C₆ alkoxy, amino, C₁-C₆alkylamino, C₂-C₁₂ dialkylamino, amido, C₁-C₆ alkylamido, C₂-C₁₂dialkylamido, —S—, —S(O)₂—, —C(O)O—, —C(O)—, —C(O)O—C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₆-C₁₀ aryl, heterocycloalkyl, or heteroaryl is optionallysubstituted with 1-3 R⁹;

each R⁹ is independently C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, heterocycloalkyl, C₆-C₁₀ aryl, heteroaryl,C₄-C₁₀ cycloalkylalkyl, heterocycloalkyl-C₁-C₆ alkyl, C₇-C₁₆ arylalkyl,heteroaryl-C₁-C₆ alkyl, halo, hydroxyl, C₁-C₆ alkoxy, C₆-C₁₀ aryloxy,C₇-C₁₆ arylalkoxy, C₂-C₈ alkoxyalkoxyl, amino, C₁-C₆ akylamino, C₂-C₁₂dialkylamino, C₁-C₆ akyl-amino-C₁-C₆ akyl, C₁-C₆ akyl-amino-C₂-C₁₂dialkyl, —S—, —S—C₁-C₆ alkyl, —S(O)₂—C₁-C₆ alkyl, sulfonamidyl, amido,urea, sulfonylurea, acyl, —C(O)—C₆-C₁₀ aryl, —NHC(O)—C₆-C₁₀ aryl,—C(O)NH—C₆-C₁₀ aryl, —C(O)OH, —C(O)O—C₁-C₆ alkyl, —C(O)—C₁-C₆ alkylacyl, nitro, or cyano;

each R^(a) is C₁-C₆ alkyl, C₁-C₆ haloalkyl, halo;

n is 1 or 2; and

m is 1, 2, or 3.

In some embodiments, Ring A is phenyl or thiazolyl.

In some embodiments, R³ is hydroxypropyl.

In another aspect, the invention provides compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

R² is C₁-C₆ alkoxy or C₆-C₁₀ aryloxy substituted with 1-3 R⁶;

R³ is C₁-C₆ heteroalkyl or C₂-C₆ hydroxyalkyl;

R⁴ is C₁-C₆ alkyl;

R⁶ is independently C₁-C₆ alkyl, halo, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or C₁-C₆ alkoxy;

each R^(a) is C₁-C₆ alkyl, C₁-C₆ haloalkyl, halo;

n is 1 or 2; and

m is 1, 2, or 3.

In some embodiments, R³ is hydroxypropyl.

In some embodiments, R^(a) is independently chloro, fluoro, or methyl.

In another aspect, the invention provides methods of treating a TRPC5mediated disorder in a subject, the method comprising administering tothe subject a compound or composition of any one of claims 23 to 33, tothereby treat the subject.

In some embodiments, the TRPC5 mediated disorder is selected from thegroup consisting of: a neuropsychiatric disorder, a neurodegenerativedisorder, nephropathy, and seizure disorder.

In certain embodiments, exemplary compounds of the invention include thecompounds described in Table A and in the Examples.

TABLE A Compound Number Structure  1

 2

 3

 4

 5

 6

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 9

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Definitions

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety selected from the Markushgroup defining the variable. For example, where a structure is describedhaving two R groups that are simultaneously present on the samecompound; the two R groups can represent different moieties selectedfrom the Markush group defined for R.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

As used herein, “acyl” refers to the group (C₁-C₆ alkyl)-C(O)—.

As used herein, “alkyl,” by itself or as part of another substituent,means, unless otherwise stated, a straight or branched chain, and canhave a number of carbon atoms optionally designated (i.e., C₁-C₆ meansone to six carbons). Examples of saturated hydrocarbon groups include,but are not limited to, groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl,homologs and isomers of, for example, n-pentyl, n-hexyl, and the like.

As used herein, “alkenyl” can be a straight or branched hydrocarbonchain, containing at least one double bond, and having from two to sixcarbon atoms (i.e. C₂-C₆ alkenyl). Examples of alkenyl groups, include,but are not limited to, groups such as ethenyl (i.e., vinyl),prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl,and the like.

As used herein, “alkoxy” can be a straight chain or branched alkoxygroup having from one to six carbon atoms (i.e., C₁-C₆ alkoxy). Examplesof alkoxy groups, include, but are not limited to, groups such asmethoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy,tert-butyloxy, pentyloxy, or hexyloxy, and the like.

As used herein, “alkynyl” can be a straight or branched hydrocarbonchain, containing at least one triple bond, having from two to sixcarbon atoms (i.e. C₂-C₆ alkynyl). Examples of alkynyl groups, include,but are not limited to, groups such as ethynyl, propynyl, butynyl,pentynyl, hexynyl, and the like.

As used herein, “amide” or “amido” refers to a chemical moiety with theformula —C(O)NR^(a)— or —NR^(a)C(O)— wherein R^(a) is H or C₁-C₆ alkyl.

As used herein, “amino” or “amine” refers to a —NH₂ radical group.

As used herein, “alkylamino” refers to a group of formula —NH(alkyl),wherein the alkyl group each has 1 to 6 carbons.

As used herein, the term “dialkylamino” refers to a group of formula—N(alkyl)₂, wherein the two alkyl groups each independently has, 1 to 6carbons.

As used herein, “aryl” refers to a polyunsaturated, aromatic,hydrocarbon moiety which can be a single ring or multiple rings (e.g., 1to 2 rings) which are fused together or linked covalently, having fromsix to twelve carbon atoms (i.e. C₆-C₁₂ aryl). Non-limiting examples ofaryl groups include phenyl, 1-naphthyl, 2-naphthyl, and 4-biphenyl.

As used herein, “arylalkyl” refers to an (aryl)alkyl-radical whereinaryl and alkyl moieties are as disclosed herein.

As used herein, “aryloxy” refers to —O-(aryl), wherein the heteroarylmoiety is as defined herein.

As used herein, “arylalkoxy” refers to —O-(arylalkyl), wherein theheteroaryl moiety is as defined herein.

As used herein, “carboxyl” refers to a —(C═O)OH radical.

As used herein, “cyano” refers to a —CN radical.

As used herein, “cycloalkyl” refers to a monocyclic or polycyclicradical that contains only carbon and hydrogen, and may be saturated, orpartially unsaturated. Cycloalkyl groups include groups having from 3 to10 ring atoms (i.e. C₃-C₁₀ cycloalkyl). Examples of cycloalkyl groupsinclude, but are not limited to, groups such as cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloseptyl,cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.

As used herein, “C₃-C₇ cycloalkyloxy” refers to —O—(C₃-C₇ cycloalkyl),wherein the C₃-C₇cycloalkyl moiety is as defined herein.

As used herein, “halo” or “halogen,” independently or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. The term “halide” by itself or as part ofanother substituent, refers to a fluoride, chloride, bromide, or iodideatom.

As used herein, “haloalkyl” and “haloalkoxy” can include alkyl andalkoxy structures that are substituted with one or more halo groups orwith combinations thereof. For example, the terms “fluoroalkyl” and“fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, inwhich the halo is fluorine.

As used herein, “heteroalkyl” can include an optionally substitutedalkyl, which has one or more skeletal chain atoms selected from an atomother than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus orcombinations thereof. A numerical range may be given, e.g. C₁-C₆heteroalkyl which refers to the number of carbons in the chain, which inthis example includes 1 to 6 carbon atoms. For example, a —CH₂OCH₂CH₃radical is referred to as a “C₃” heteroalkyl. Connection to the rest ofthe molecule may be through either a heteroatom or a carbon in theheteroalkyl chain.

As used herein, “heteroaryl” refers to a 5- to 14-membered aromaticradical (e.g., C₂-C₁₃ heteroaryl) that includes one or more ringheteroatoms selected from nitrogen, oxygen and sulfur, and which may bea monocyclic or bicyclic ring system. Bivalent radicals derived fromunivalent heteroaryl radicals whose names end in “-yl” by removal of onehydrogen atom from the atom with the free valence are named by adding“-idene” to the name of the corresponding univalent radical, e.g., apyridyl group with two points of attachment is a pyridylidene. AnN-containing “heteroaromatic” or “heteroaryl” moiety refers to anaromatic group in which at least one of the skeletal atoms of the ringis a nitrogen atom. The polycyclic heteroaryl group may be fused ornon-fused. The heteroatom(s) in the heteroaryl radical is optionallyoxidized. One or more nitrogen atoms, if present, are optionallyquaternized. The heteroaryl is attached to the rest of the moleculethrough any atom of the ring(s). Examples of heteroaryl groups includewithout limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, furyl (furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl,thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl,benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl,1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl,benzimidazolyl, indolinyl, and the like.

As used herein, “heteraryloxy” refers to —O-(heteroaryl), wherein theheteroaryl moiety is as defined herein.

As used herein, “heterocycloalkyl” can be a stable 3- to 18-memberednon-aromatic ring radical that comprises two to twelve carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.Examples of heterocycloalkyl groups include, but are not limited to,groups such as dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl, and the like.

As used herein, “hydroxy” or “hydroxyl” refers to —OH.

As used herein, “hydroxyalkyl” refers to an alkyl group having 1 to 6carbon atoms, which is substituted with a hydroxyl group, e.g.,hydroxypropyl.

As used herein, “cyano” refers to —CN.

As used herein, “nitro” refers to —NO₂.

As used herein, “urea” refers to —NR^(a)—C(O)—NR^(a) ₂ or—NR^(a)—C(O)NR^(a)—, wherein R^(a) is H or C₁-C₆ alkyl.

As used herein, “sulfonylurea” refers to —S(O)₂—NR^(a)—C(O)—NR^(a)— or—NR^(a)—C(O)—NR^(a)—SO₂—, wherein R^(a) is H or C₁-C₆ alkyl.

As used herein, “sulfonamidyl” refers to —S(O)₂—NR^(a)— or—NR^(a)—S(O)₂—, wherein R^(a) is H or C₁-C₆ alkyl.

The terms “antagonist” and “inhibitor” are used interchangeably to referto an agent that decreases or suppresses a biological activity, such asto repress an activity of an ion channel, such as TRPC5. TRPC5 ionchannels as described herein include homomultimeric and heteromultimericstructures (e.g., homomultimeric TRPC5 and heteromeric TRPC5-TRPC1 orTRPC5-TRPC4). TRPC5 antagonists include inhibitors having anycombination of the structural and/or functional properties disclosedherein.

An “effective amount” of, e.g., a TRPC5 antagonist, with respect to thesubject methods of inhibition or treatment, refers to an amount of theantagonist in a preparation which, when applied as part of a desireddosage regimen brings about a desired clinical or functional result.Without being bound by theory, an effective amount of a TRPC5 antagonistfor use in the methods of the present invention includes an amount of aTRPC5 antagonist effective to decrease one or more in vitro or in vivofunction of a TRPC5 channel. Exemplary functions include, but are notlimited to, membrane polarization (e.g., an antagonist may promotehyperpolarization of a cell), ion flux, ion concentration in a cell,outward current, and inward current. Compounds that antagonize TRPC5function include compounds that antagonize an in vitro or in vivofunctional activity of TRPC5. When a particular functional activity isonly readily observable in an in vitro assay, the ability of a compoundto inhibit TRPC5 function in that in vitro assay serves as a reasonableproxy for the activity of that compound. In certain embodiments, aneffective amount is an amount sufficient to inhibit a TRPC5-mediatedcurrent and/or the amount sufficient to inhibit TRPC5 mediated ion flux.

The TRPC5 antagonists for use in the methods of the present inventionmay be characterized according to their activity, or lack of activity,against one or more other ion channels. When other ion channels arereferred to, inhibition of a function of such other ion channels isdefined similarly. For example, inhibition of an ion channel or anactivity of an ion channel means the antagonist inhibits one or morefunctional activities of the other ion channel. Such functions includethe current mediated by the particular ion channel, ion flux, ormembrane polarization.

The term “preventing” is art-recognized, and when used in relation to acondition, such as a local recurrence, a disease such as cancer, asyndrome complex such as heart failure or any other medical condition,is well understood in the art, and includes administration of acomposition which reduces the frequency of, or delays the onset of,symptoms of a medical condition in a subject relative to a subject whichdoes not receive the composition. Thus, prevention of cancer includes,for example, reducing the number of detectable cancerous growths in apopulation of patients receiving a prophylactic treatment relative to anuntreated control population, and/or delaying the appearance ofdetectable cancerous growths in a treated population versus an untreatedcontrol population, e.g., by a statistically and/or clinicallysignificant amount. Prevention of an infection includes, for example,reducing the number of diagnoses of the infection in a treatedpopulation versus an untreated control population, and/or delaying theonset of symptoms of the infection in a treated population versus anuntreated control population. Prevention of pain includes, for example,reducing the magnitude of, or alternatively delaying, pain sensationsexperienced by subjects in a treated population versus an untreatedcontrol population.

The term “prodrug” is intended to encompass compounds that, underphysiological conditions, are converted into the therapeutically activeagents of the present invention. A common method for making a prodrug isto include selected moieties that are hydrolyzed under physiologicalconditions to reveal the desired molecule. In other embodiments, theprodrug is converted by an enzymatic activity of the host animal.

The term “small molecule” refers to a compound having a molecular weightless than about 2500 amu, preferably less than about 2000 amu, even morepreferably less than about 1500 amu, still more preferably less thanabout 1000 amu, or most preferably less than about 750 amu.

The terms “TRPC5”, “TRPC5 protein”, and “TRPC5 channel” are usedinterchangeably throughout the application. Unless expressly stated, theterm TRPC5 includes homomultimeric structures (e.g., homomultimericTRPC5) and heteromultimeric structures (e.g., heteromultimericTRPC5-TRPC1).

The term “oxidative metabolite” is intended to encompass compounds thatare produced by metabolism of the parent compound under normalphysiological conditions. Specifically, an oxidative metabolite isformed by oxidation of the parent compound during metabolism. Forexample, a thioether group may be oxidized to the correspondingsulfoxide or sulfone.

The term “solvate” as used herein, refers to a compound formed bysolvation (e.g., a compound formed by the combination of solventmolecules with molecules or ions of the solute).

The term “hydrate” as used herein, refers to a compound formed by theunion of water with the parent compound.

The term “treating” includes prophylactic and/or therapeutic treatments.The term “prophylactic or therapeutic” treatment is art-recognized andincludes administration to the host of one or more of the subjectcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thehost animal) then the treatment is prophylactic, (i.e., it protects thehost against developing the unwanted condition), whereas if it isadministered after manifestation of the unwanted condition, thetreatment is therapeutic, (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The terms “compound” and “agent” are used interchangeably to refer tothe inhibitors/antagonists of the invention. In certain embodiments, thecompounds are small organic or inorganic molecules, e.g., with molecularweights less than 7500 amu, preferably less than 5000 amu, and even morepreferably less than 2000, 1500, 1000, or 600 amu. Such compounds canbind to and inhibit a function of TRPC5. In certain other embodiments,the compounds are nucleic acids, for example, TRPC5 antisenseoligonucleotides or TRPC5 RNAi constructs. Such compounds can inhibitthe expression of TRPC5, thereby inhibiting the activity of TRPC5. Otherexemplary compounds that may act as inhibitors include ribozymes andpeptide fragments.

Contemplated equivalents of the compounds described above includecompounds which otherwise correspond thereto, and which have the samegeneral properties thereof (e.g., the ability to antagonize TRPC5activity), wherein one or more simple variations of substituents aremade which do not adversely affect the efficacy of the compound. Ingeneral, the compound of the present invention may be prepared by themethods illustrated in the general reaction schemes as, for example,described below, or by modifications thereof, using readily availablestarting materials, reagents and conventional synthesis procedures. Inthese reactions, it is also possible to make use of variants which arein themselves known, but are not mentioned here.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Alsofor purposes of this invention, the term “hydrocarbon” is contemplatedto include all permissible compounds having at least one hydrogen andone carbon atom. In a broad aspect, the permissible hydrocarbons includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and nonaromatic organic compounds which can besubstituted or unsubstituted.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a “chiral resolving acid” which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art. Compounds of the invention alsoinclude tautomeric forms, such as keto-enol tautomers.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. For example, thecompound of the invention may be radiolabeled with radioactive isotopes,such as for example tritium (³H) or carbon-14 (¹⁴C). All isotopicvariations, whether radioactive or not, are intended to be encompassedwithin the scope of the present invention.

Compounds of the invention can exist in unsolvated forms as well assolvated forms, including hydrated forms. In general, the solvated formsare equivalent to unsolvated forms and are encompassed within the scopeof the present invention. A compound of formula (I) may exist inmultiple crystalline or amorphous forms. In general, all physical formsare equivalent for the uses contemplated by the present invention andare intended to be within the scope of the present invention.

The term “pharmaceutically acceptable salts” includes salts of acompound of the invention which are prepared with relatively nontoxicacids or bases. Base addition salts can be obtained by contacting theneutral form of a compound of the invention with a sufficient amount ofthe desired base, either neat or in a suitable inert solvent. Examplesof pharmaceutically acceptable base addition salts include sodium,potassium, calcium, ammonium, organic amino, or magnesium salt, or asimilar salt. Acid addition salts can be obtained by contacting theneutral form of compound of the invention with a sufficient amount ofthe desired acid, either neat or in a suitable inert solvent. Examplesof pharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, trifluoroacetic,propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic,fumaric, lactic, mandelic, phthalic, benzensulfonic, p-tolylsulfonic,citric, tartaric, methanesulfonic, and the like. Also included are thesalts of amino acids such as arginate and the like, and salts of organicacids like glucuronic or galactunoric acids and the like (see, forexample, Berge et al., “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19).

The neutral forms of compound of the invention is preferably regeneratedby contacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentinvention.

The term “low enough pyrogen activity”, with reference to apharmaceutical preparation, refers to a preparation that does notcontain a pyrogen in an amount that would lead to an adverse effect(e.g., irritation, fever, inflammation, diarrhea, respiratory distress,endotoxic shock, etc.) in a subject to which the preparation has beenadministered. For example, the term is meant to encompass preparationsthat are free of, or substantially free of, an endotoxin such as, forexample, a lipopolysaccharide (LPS).

Diseases, Disorders, or Conditions Related to TRPC5 Function

In certain embodiments, the invention provides methods and compositionsfor antagonizing a function of a TRPC5 channel in vitro or in vivo.Exemplary functions include, but are not limited to, TRPC5-mediatedcurrent. In certain embodiments, the invention provides methods fortreating a disease or disorder or condition by administering compound ofthe invention. In other embodiments, the compound of formula (I)selectively inhibits the expression level and/or activity of a TRPC5protein. In other words, in certain embodiment, the compound of theinvention inhibits the activity of a TRPC5 protein preferentially incomparison to the activity of one or more other ion channels.

Treatment of Anxiety and Fear-Related Disorders

In certain embodiments, the compound of the invention can be used forpreventing or treating anxiety and fear-related disorders (see, e.g.,Riccio et al. (2009) Cell 137:761-72). Examples of such disordersinclude post-traumatic stress disorder, panic disorder, agoraphobia,social phobias, generalized anxiety disorder, panic disorder, socialanxiety disorder, obsessive-compulsive disorder, and separation anxiety.

Memory, Motion and Mood Disorders

A compound of the invention is also useful for the treatment ofParkinson's disease, epilepsy, memory disorders, stroke, seizure, andmood disorders. Mood disorders include depression (e.g., majordepression, psychiatric depression, dysthymia, and postpartumdepression) and bipolar disorder (e.g., bipolar I, bipolar II, andcyclothymia). Memory disorders are conditions associated with any memoryloss and may result from Alzheimer's disease, amnesia, aphasia,atherosclerosis, brain injury or disorder, brain tumor, chronic fatiguesyndrome, Creutzfedt-Jacob disease, dissociative amnesia, depression,fuge amnesia, Huntington's disease, learning disorders, sleepingdisorders, multiple personality disorder, pain, post-traumatic stressdisorder, schizophrenia, sports injuries, stroke, and Wernicke-Korsakoffsyndrome.

Treatment of Pain, Sensitivity to Pain and Touch, or Pain-RelatedDiseases or Disorders

In certain embodiments, a compound of the invention is used to treat orameliorate pain. Exemplary classes of pain that can be treated using acompound of formula (I)include, but are not limited to nociceptive pain,inflammatory pain, and neuropathic pain. The pain can be chronic oracute.

A compound of the invention may be particularly useful in the treatmentof pain associated with cancer, osteoarthritis, rheumatoid arthritis,post-herpetic neuralgia, burns, and other indications detailed above. Tofurther illustrate, additional exemplary indications for which acompound of the invention can be used include oral pain, pelvic pain,Fabry's disease, complex regional pain syndrome, pancreatitis, andfibromyalgia syndrome.

A compound of the invention may also be used in connection withprevention or treatment of sensitivity to pain and touch. Pain orsensitivity to pain and touch may be indicated in a variety of diseases,disorders or conditions, including, but not limited to, diabeticneuropathy, breast pain, psoriasis, eczema, dermatitis, burn,post-herpetic neuralgia (shingles), nociceptive pain, peripheralneuropathic and central neuropathic pain, chronic pain, cancer and tumorpain, spinal cord injury, crush injury and trauma induced pain,migraine, cerebrovascular and vascular pain, sickle cell disease pain,rheumatoid arthritis pain, musculoskeletal pain including treating signsand symptoms of osteoarthritis and rheumatoid arthritis, orofacial andfacial pain, including dental, temperomandibular disorder, and cancerrelated, lower back or pelvic pain, surgical incision related pain,inflammatory and non-inflammatory pain, visceral pain, psychogenic painand soft tissue inflammatory pain, fibromyalgia-related pain, and reflexsympathetic dystrophy, and pain resulting from kidney stones or urinarytract infection.

The foregoing are merely exemplary of diseases and conditions that causeor lead to inflammation, lesions, ulcers, or other sources of oral pain.In other embodiments, the oral pain is due to an injury to the mouth,jaw, lips, gums, or teeth. In other embodiments, the oral pain is due tooral surgery, for example, surgery for cancer, tooth extraction, or jawremodeling. Other conditions that may lead to oral ulcers, and thus oralpain, include, but are not limited to chickpox, herpes zoster,infectious mononucleosis, syphilis, tuberculosis, acute necrotizinggingivitis, and burning mouth syndrome.

Fibromyalgia (FMS; fibromyalgia syndrome) is a widespreadmusculoskeletal pain and fatigue disorder. Fibromyalgia is characterizedby pain in the muscles, ligaments, and tendons. The condition affectsmore women than men, and occurs in people of all ages. Overall, FMS isestimated to afflict 3-6% of the population. Patients have described thepain associated with fibromylagia as deep muscular aching, throbbing,shooting, and stabbing. The pain sometimes includes an intense burningsensation. The pain and stiffness are often worse in the morning orafter repetitive use of a particular muscle group.

Additionally, varying levels of fatigue ranging from mild toincapacitating are often associated with fibromylagia. Other symptoms offibromylagia include gastrointestinal symptoms. Irritable bowel syndromeand IBS-like symptoms such as constipation, diarrhea, frequent abdominalpain, abdominal gas, and nausea occur in roughly 40 to 70% of FMSpatients. Acid reflux or gastroesophogeal reflux disease (GERD) occursat a similar frequency.

Complex Regional Pain Syndrome (CRPS; also known as chronic regionalpain syndrome) is a chronic pain condition. CRPS was formerly known asreflex sympathetic dystrophy (RSD). CRPS is a chronic, painful, andprogressive neurological condition that affects skin, muscles, joints,and bones. The syndrome usually develops in an injured limb, such as abroken leg or following surgery. However, many cases involve only aminor injury, such as a sprain, and sometimes no precipitating injuriousevent can be identified. CRPS involves continuous, intense pain that isdisproportionate to the severity of the injury. The pain worsens, ratherthan improves, over time.

Although CRPS can affect a variety of regions of the body, it most oftenaffects the arms, legs, hands, or feet. Often the pain begins in oneportion of a limb, but spreads over time to include the entire limb oreven to include a different limb. Typical features include dramaticchanges in the color and temperature of the skin over the affected limbor body part, accompanied by intense burning pain, skin sensitivity,sweating, and swelling.

The compounds disclosed herein can also be used to treat endometriosisand the pain associated therewith.

Neurological or Neurodegenerative Diseases and Disorders

Neurodegenerative diseases and disorders include but are not limited toAlzheimer's disease (AD), Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis (ALS), and other brain disorders caused bytrauma or other insults including aging.

Mechanisms associated with calcium signaling may be altered in manyneurodegenerative diseases and in disorders resulting from brain injury.For example, fibroblasts or T-lymphocytes from patients with AD haveconsistently displayed an increase in Ca²⁺ release from intracellularstores compared to controls (Ito et al. (1994) Proc. Natl. Acad. Sci.U.S.A. 91:534-538; Gibson et al. (1996) Biochem. Biophys. ACTA1316:71-77; Etchenberrigaray et al. (1998) Neurobiology of Disease,5:37-45). Consistent with these observations, mutations in presenilingenes (PS1 or PS2) associated with familial AD (FAD) have been shown toincrease InsP3-mediated Ca²⁺ release from internal stores (Guo et al.(1996) Neuro Report, 8:379-383; Leissring et al. (1999) J.Neurochemistry, 72:1061-1068; Leissring et al. (1999) J. Biol. Chem. 274(46):32535-32538; Leissring et al. (2000) J. Cell Biol. 149 (4):793-797;Leissring et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97(15):8590-8593). Furthermore, mutations in PS1 or PS2 associated with anincrease in amyloidogenic amyloid β peptide generation in AD arereported to be associated with a decrease in intracellular calcium level(Yoo et al. (2000) Neuron, 27 (3):561-572).

Experimental traumatic brain injury has been shown to initiate massivedisturbances in Ca²⁺ concentrations in the brain that may contribute tofurther neuronal damage. Intracellular Ca²⁺ may be elevated by manydifferent ion channels. It has been further shown that channel blockersmay be beneficial in the treatment of neurological motor dysfunctionwhen administered in the acute posttraumatic period (Cheney et al.(2000) J. Neurotrauma, 17 (1):83-91).

Seizure

Excitotoxicity of a variety of origins leads to seizures. Commonlyexcess neuronal firing can drive seizure activity. Compounds that reducethe hyperexcitability of relevant neuronal populations have significantpotential in reducing seizure activity. Compounds of the invention thatinhibit TRPC5 may reduce hyperexcitability and thus reduce seizureactivity.

Proteinuric Kidney Disease

TRPC5 is also expressed in the podocyte of the kidney. It has beenproposed that there is an antagonistic regulation of actin dynamics andcell in the podocytes by TRPC5 and TRPC6 (Tian et al., (2010) ScienceSignaling). Thus, inhibiting TRPC5 may impact the reaction of thepodocyte to injury.

Combination Therapy

The present invention provides compounds of the invention for use invitro and in vivo. The present invention also provides compositions andpharmaceutical compositions comprising a compound of formula (I) thatinhibits TRPC5 activity. In certain embodiments, the compound of theinvention is selective. In other words, in certain embodiments, thecompound of the invention inhibits TRPC5 activity preferentially overthe activity of other ion channels. In certain embodiments, the compoundof formula (I) inhibits TRPC5 activity preferentially over TRPV1, TRPV2,TRPV3, TRPV4, TRPC3, TRPC6, TRPC7, TRPA1, and/or TRPM8 activity. Forexample, in certain embodiments, the compound of formula (I) inhibitsthe activity of TRPC5 and also inhibits the activity of one or more ofTRPC4, TRPV1, TRPV2, TRPV3, TRPV4, TRPC3, TRPC6, TRPC7, TRPA1, andTRPM8.

A compound of the invention can be used alone or in combination withother pharmaceutically active agents. Examples of such otherpharmaceutically active agents include, but are not limited to,anti-depressants, anti-anxiety agents, anti-epileptic agents,anti-inflammatory agents (e.g., NSAIDS, bradykinin receptor antagonists,hormones and autacoids such as corticosteroids), or anti-migraineagents. Certain active agents belong to more than one category.

In certain embodiments, a compound of the invention is conjointlyadministered with an analgesic. Suitable analgesics include, but are notlimited to, opioids, glucocorticosteroids, non-steroidalanti-inflammatories, naphthylalkanones, oxicams, para-aminophenolderivatives, propionic acids, propionic acid derivatives, salicylates,fenamates, fenamate derivatives, pyrozoles, and pyrozole derivatives.Examples of such analgesic compounds include, but are not limited to,codeine, hydrocodone, hydromorphone, levorpharnol, morphine, oxycodone,oxymorphone, butorphanol, dezocine, nalbuphine, pentazocine, etodolac,indomethacin, sulindac, tolmetin, nabumetone, piroxicam, acetaminophen,fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, diclofenac,oxaprozin, aspirin, diflunisal, meclofenamic acid, mefanamic acid,prednisolone, and dexamethasone. Preferred analgesics are non-steroidalanti-inflammatories and opioids (preferably morphine).

In some embodiments, a compound of the invention can be administered inconjunction with a therapeutic whose administration causes pain. Forexample, a compound of the invention can be administered in conjunctionwith an anesthetic, to reduce the pain caused by the administration ofthe anaesthetic. A compound of the invention can also be administered inconjunction with a chemotherapeutic agent, to reduce the pain caused byadministration of the chemotherapeutic agent.

In certain embodiments, a compound of the invention is conjointlyadministered with a non-steroidal anti-inflammatory. Suitablenon-steroidal anti-inflammatory compounds include, but are not limitedto, piroxicam, diclofenac, etodolac, indomethacin, ketoralac, oxaprozin,tolmetin, naproxen, flubiprofen, fenoprofen, ketoprofen, ibuprofen,mefenamic acid, sulindac, apazone, phenylbutazone, aspirin, celecoxiband rofecoxib.

Pharmaceutical Compositions

While it is possible for a compound of the invention to be administeredalone, it is preferable to administer the compound as a pharmaceuticalformulation, where the compound is combined with one or morepharmaceutically acceptable excipients or carriers. The compound of theinvention may be formulated for administration in any convenient way foruse in human or veterinary medicine. In certain embodiments, thecompound of the invention may be a prodrug, e.g., capable of beingconverted to an active compound in a physiological setting.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Examples of pharmaceutically acceptable carriers include: (1) sugars,such as lactose, glucose and sucrose; (2) starches, such as corn starchand potato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21)cyclodextrins such as Captisol®; and (22) other non-toxic compatiblesubstances employed in pharmaceutical formulations.

Examples of pharmaceutically acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders,granules and the like) can include one or more pharmaceuticallyacceptable carriers, such as sodium citrate or dicalcium phosphate,and/or any of the following: (1) fillers or extenders, such as starches,lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders,such as, for example, carboxymethylcellulose, alginates, gelatin,polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, cetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents.

Liquid dosage forms can include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the compound of the invention, the liquid dosage forms may containinert diluents commonly used in the art, such as, for example, water orother solvents, solubilizing agents and emulsifiers, such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils(in particular, cottonseed, groundnut, corn, germ, olive, castor andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the compound of the invention, may containsuspending agents as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Ointments, pastes, creams and gels may contain, in addition to thecompound of the invention, excipients, such as animal and vegetablefats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compound of theinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Theamount of a compound of the invention which can be combined with acarrier material to produce a single dosage form will vary dependingupon the host being treated, the particular mode of administration. Theamount of a compound of the invention that can be combined with acarrier material to produce a single dosage form will generally be thatamount of the compound which produces a therapeutic effect. Generally,out of one hundred percent, this amount will range from about 1 percentto about ninety-nine percent of a compound of the invention, preferablyfrom about 5 percent to about 70 percent, most preferably from about 10percent to about 30 percent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions disclosed herein, such as dragees, capsules, pills andgranules, may optionally be scored or prepared with coatings and shells,such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containpacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions that can be used include polymeric substances andwaxes. The active ingredient can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Dosage forms for the topical or transdermal administration of a compoundof the invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that may berequired.

The formulations disclosed herein can be delivered via a device.Exemplary devices include, but are not limited to, a catheter, wire,stent, or other intraluminal device. Further exemplary delivery devicesalso include a patch, bandage, mouthguard, or dental apparatus.Transdermal patches have the added advantage of providing controlleddelivery of a compound of the invention to the body. Such dosage formscan be made by dissolving or dispersing the compound of the invention inthe proper medium. Absorption enhancers can also be used to increase theflux of the compound across the skin. The rate of such flux can becontrolled by either providing a rate controlling membrane or dispersingthe compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, drops, solutions and the like,are also contemplated as being within the scope of this invention.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

When a compound of the invention is administered as a pharmaceutical, tohumans and animals, it can be given per se or as a pharmaceuticalcomposition containing, for example, 0.1 to 99.5% (more preferably, 0.5to 90%) of the compound of the invention in combination with apharmaceutically acceptable carrier.

The formulations can be administered topically, orally, transdermally,rectally, vaginally, parentally, intranasally, intrapulmonary,intraocularly, intravenously, intramuscularly, intraarterially,intrathecally, intracapsularly, intraorbitally, intracardiacly,intradermally, intraperitoneally, transtracheally, subcutaneously,subcuticularly, intraarticularly, subcapsularly, subarachnoidly,intraspinally, intrasternally, sublingually, or by inhalation.

Dosages

Actual dosage levels of the compound of the invention in thepharmaceutical compositions of this invention may be varied so as toobtain an amount of the active ingredient that is effective to achievethe desired therapeutic response for a particular patient, composition,and mode of administration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the compound of the invention disclosed hereinemployed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compound of the invention in the pharmaceuticalcomposition at levels lower than that required in order to achieve thedesired therapeutic effect and gradually increase the dosage until thedesired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound that is the lowest dose effective to producea therapeutic effect. Such an effective dose will generally depend uponthe factors described above. Generally, intravenous,intracerebroventricular and subcutaneous doses of the compounds of theinvention for a patient will range from about 0.0001 to about 100 mg perkilogram of body weight per day. For example, the dose can be 0.1-50,0.1-25, 0.5-10, 1-10, or 5-10 mg/kg.

If desired, the effective daily dose of the compound of the inventionmay be administered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

Disease and Injury Models

A compound of the invention which antagonizes TRPC5 function may beuseful in the prophylaxis and treatment of any of the foregoinginjuries, diseases, disorders, or conditions. In addition to in vitroassays of the activity of the compound of the invention, its efficacycan be readily tested in one or more animal models. By way of example,numerous well known animal models exist. One or more suitable animalmodels (e.g., suitable in light of the particular indication) can beselected.

Fear-related behaviors can be measured as described, e.g., in Riccio etal. Pain behaviors can be studied using various agents or procedures tosimulate pain resulting from injuries, diseases, or other conditions.Blackburn-Munro (2004) Trends in Pharmacological Sciences 25: 299-305(see, for example, Table 1). Behavioral characteristics of challengedanimals can then be observed. Compounds or procedures that may reducepain in the animals can be readily tested by observing behavioralcharacteristics of challenged animals in the presence versus the absenceof the test compound(s) or procedure.

Exemplary behavioral tests used to study chronic pain include tests ofspontaneous pain, allodynia, and hyperalgesia. Id. To assess spontaneouspain, posture, gait, nocifensive signs (e.g., paw licking, excessivegrooming, excessive exploratory behavior, guarding of the injured bodypart, and self-mutilation) can be observed. To measure evoked pain,behavioral responses can be examined following exposure to heat (e.g.,thermal injury model).

Exemplary animal models of pain include, but are not limited to, theChung model, the carageenan induced hyperalgesia model, the Freund'scomplete adjuvant induced hyperalgesia model, the thermal injury model,the formalin model and the Bennett Model. The Chung model of neuropathicpain (without inflammation) involves ligating one or more spinal nerves.Chung et al. (2004) Methods Mol Med 99: 35-45; Kim and Chung (1992) Pain50: 355-363. Ligation of the spinal nerves results in a variety ofbehavioral changes in the animals including heat hyperalgesia, coldallodynia, and ongoing pain. Compounds that antagonize TRPC5 can beadministered to ligated animals to assess whether they diminish theseligation-induced behavioral changes in comparison to that observed inthe absence of compound.

Useful anxiety and depression models include the maternal separationmodel, the elevated plus-maze model, the forced swim test, the tailsuspension test, the light/dark preference model, the light-enhancedstartle model, and the ultrasonic vocalization model.

Useful seizure models include but are not limited to maximal electricshock (MES), acoustic startle in susceptible animals (eg DBA mice), andchemical induced seizure (with proconvulsant compounds such aspilocarpine, pentalene tetrazole, kainic acid, N-methyl-D-asparticacid).

Useful models of kidney function include the LPS-induced proteinuria(waiting for a reference for others).

EXAMPLES Example 1: Patch Clamp Experiments

Patch clamp experiments permit the detection of currents through theTRPC5 channel in the cell line described above. In normal whole-cellpatch clamp recordings, a glass electrode is brought into contact with asingle cell and a high-resistance (gigaohm) seal is established with thecell membrane. The membrane is then ruptured to achieve the whole-cellconfiguration, permitting control of the voltage of the cell membraneand measurement of currents flowing across the membrane using theamplifier attached to the electrode and resulting in the replacement ofcytoplasm with the pipette solution. A perfusion system permits controlof the extracellular solution, including the addition of blockers andactivators of the current. The current can be activated by including 1.4μM free Ca²⁺ in the pipette (intracellular) solution, and 80 μM LaCl₃ inthe extracellular solution.

TRPC5 cells were induced 20-48 hours, removed from growth plates, andreplated at low density (to attain good single-cell physical separation)on glass coverslips for measurement. In some cases, cells were grown inlow density overnight on glass coverslips. Patch clamp recordings weremade in the whole-cell mode with a holding potential of −40 mV. Every 5seconds, a voltage ramp was applied from −120 to +100 mV, 400 ms induration. Currents elicited were quantified at −80 mV and +80 mV. Theinternal solution consisted of 140 mM cesium aspartate, 10 mM HEDTA, 2mM CaCl₂, 2.27 mM MgCl₂ and 10 mM HEPES, pH 7.2, with 1,400 nMcalculated free Ca²⁺. The external solution consisted of 150 mM NaCl,4.5 mM KCl, 1 mM MgCl₂, 2 mM CaCl₂, 10 mM HEPES, 10 mM glucose, 1 mMEGTA, pH 7.4. Upon addition of LaCl₃, TRPC5 current was induced only inTRPC5-expressing cells and not in parental HEK293 TREx cells. Removal ofthe LaCl₃ stimulus causes most of the current to go away. Potentialblockers were tested for ability to block both inward and outwardcurrents in the continued presence of LaCl₃.

IC₅₀ of a compound of the invention was estimated by testing thecompound at 5 μM and 500 nM. When 5 μM of a compound showed no block,IC₅₀ was estimated as >10 μM. When 5 μM of a compound showed 50% or lessblock, a rough estimate of IC₅₀ in the range of 5-10 μM could be made.IC₅₀ for a compound of Formula I or Formula II between 500 nM and 5 μMwas similarly estimated.

A compound described herein may be tested for its ability to block bothinward and outward currents through the TRPC5 channel, e.g., by an assayas described in Example 1. For example, IC₅₀ of a compound of theinvention was estimated by testing the compound at 5 μM and 500 nM. When5 μM of a compound showed no block, IC₅₀ was estimated as >10 μM. When 5μM of a compound showed 50% or less block, a rough estimate of IC₅₀ inthe range of 5-10 μM could be made. IC₅₀ for a compound of the inventionbetween 500 nM and 5 μM was similarly estimated. Exemplary compounds areshown in Table B below. As shown in Table B, “A” refers to an IC₅₀<100nM. “B” refers to an IC₅₀ between 100 nM and 500 nM. “C” refers to anIC₅₀ between 500 nM and 1000 nM. “D” refers to an IC₅₀ between 1 μM and2 μM. “E” refers to an IC₅₀ between 2 μM and 10 μM. “F” refers toagonist compounds. “ND” refers to compounds wherein the IC₅₀ was notdetermined.

TABLE B hTRPC4 Patch Inwd Compound (nM) Number (All Batches)  11

A  15

F  30

A  77

ND  82

A 115

F 129

ND 139

F 145

A 161

A 166

F 168

F 198

F 255

B 260

A 263

ND 415

F 485

A 587

A

Example 2

General Procedures

All reagents were purchased from commercial suppliers and used withoutfurther purification unless otherwise stated. THF was continuouslyrefluxed and freshly distilled from sodium and benzophenone undernitrogen, DCM was continuously refluxed and freshly distilled from CaH₂under nitrogen.

Reactions were monitored via TLC on silica gel plates (either 60 HSGF254percolated plates (0.15-0.2 mm SiO₂) or Baker-flex IB2-F TLC plates),and visualized using UV light (254 nm or 365 nm) and/or staining with asolution of DNP (12 g, 2,4-dinitrofenylhydrazin, 60 mL concentratedH₂SO₄, 80 ml H₂O, 200 mL ethanol) and subsequent heating or monitoredvia LCMS.

Microwave reactions were carried out with a Biotage Smith Synthesizer.

LCMS were performed on a SHIMADZU LCMS-2010EV instrument using one oftwo sets of conditions. LCMS conditions one: (Chromolith SpeedROD,RP-18e column, 50×4.6 mm, mobile phase: Solvent A:CH₃CN/H₂O/HCOOH=10/90/0.05, Solvent B: CH₃CN/H₂O/HCOOH=90/10/0.05, 0.8min@10% B, 2.7 min gradient (10-95% B), then 0.8 min @95% B, Flow rate:3 mL/min, temperature: 40° C.). LCMS conditions two: (Zorbax, 3.5micron, 2.1×50 mm C18 column. Mobile phase: Solvent A: 0.1% formicacid/acetonitrile Solvent B: 0.1% formic acid/water. Gradient: 5% to 95%B using a 5 min or 8 min runtime).

Preparative HPLC were performed either on a SHIMADZU LC-8A instrument.(Column: YMC Pack ODS-A (150*30 mm, 10 μm)) or LC-6AD (Column: Shim=PackPREP-ODS-H (250*20 mm, 10 μm)) with UV detection which were controlledby LC solution Chemstation software. H₂O (0.1% HCOOH) and methanol(MeCN) as mobile phase at the indicated flow rate.

Analytical HPLC were performed on a SHIMADZU LC-2010A instrument.(Chromolith SpeedROD, RP-18e, 50×4.6 mm, mobile phase: Solvent A:CH₃CN/H₂O/HCOOH=10/90/0.05, Solvent B: CH₃CN/H₂O/HCOOH=90/10/0.05, 0.8min@10% B, 2.7 min gradient (10-95% B), then 0.8 min@95% B, Flow rate: 3mL/min, temperature: 40° C.).

¹H-NMR spectra were recorded on either a Bruker Avance II 400 MHz or aVarian Unity Inova 400 MHz instrument. Chemical shifts (δ) are reportedin ppm relative to tetramethylsilane (δ=0.000 ppm) and the spectra werecalibrated to the residual solvent signal of chloroform (δ=7.26),Dimethyl sulfoxide (δ=2.50), methanol (δ=3.30). Data for ¹H-NMR spectraare reported as follows: chemical shift (multiplicity, number ofhydrogens). Abbreviations are as follows: s (singlet), d (doublet), t(triplet), q (quartet), quint (quintet), m (multiplet), br (broad).

LIST OF ABBREVIATIONS AND TERMS

-   BPO benzoyl peroxide-   CDI carbonyldiimidazole-   Chromatography compound purification using silica gel-   Concentrated [or concentrated at reduced pressure] solvent removal    with the aid of a rotary evaporation device-   DCM dichloromethane-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   Dess Martin [or Dess Martin periodinane]    1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one-   Dilute HCl 1N hydrochloric acid-   DMF N,N-dimethylformamide-   DMAP 4-dimethylaminopyridine-   Dried, referring to removal of residual water from organic solutions    implies the use of an inorganic drying agent such as sodium sulfate-   Dried in vacuo [or dried under vacuum] residual solvent removal with    the aid of a vacuum pump-   DMSO dimethyl sulfoxide-   Eaton's reagent 7.7 wt % phosphorus pentoxide in methanesulfonic    acid-   EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide)-   Evaporated solvent removal with the aid of a rotary evaporation    device-   h hour-   HMDS hexamethyldisilazane-   LAH lithium aluminum hydride-   MCPBA 3-chloroperoxybenzoic acid-   min minutes-   n-BuLi n-Butyllithium-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NMP N-methylpyrolidinone-   Oxone potassium peroxomonosulfate-   Pd/C palladium on activated carbon-   Pd-dppf 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride    dichloromethane complex-   PMB 4-methoxybenzyl-   PPTS pyridinium p-toluenesulfonate-   Preparative TLC preparative thin layer chromatography-   SEM (trimethylsilyl)ethoxy)methyl-   TBAI tetrabutylammonium iodide-   TBAF tetrabutylammonium fluoride-   TBAH tetrabutylammonium hydroxide-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrafuran-   tlc thin layer chromatography on silica gel-   X-phos 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl    Purine Numbering

Preparation of Intermediates

Intermediate 1 2-(2-(2-chloroethoxy)ethoxy)tetrahydro-2H-pyran

To a solution of 2-(2-chloroethoxy)ethanol (10 g, 0.071 mol) in DCM (150mL) was added PPTS (891 mg, 3.6 mmol), then dihydropyran (10.2 g, 0.107mol) was added dropwise at 0° C. The mixture was stirred at roomtemperature for 16 h. It was partitioned between DCM and water. Theorganic phase was washed with brine, dried over sodium sulfate, filteredand concentrated to give a crude product which was purified by silicagel chromatography eluted with petroleum ether to give2-(2-bromoethoxy)tetrahydro-2H-pyran(11.9 g, 79.8% yield) as lightyellow oil. ¹H-NMR (CDCl₃) δ 4.65-4.67 (t, 1H), 3.86-3.92 (m, 2H),3.78-.381 (m, 2H), 3.71-3.73 (t, 2H), 3.64-3.67 (t, 2H), 1.77-1.87 (m,2H), 1.51-1.64 (m, 6H).

Intermediate 2 2-(2-bromoethoxy)tetrahydro-2H-pyran

To a solution of 2-bromoethanol (15 g, 0.12 mol) in DCM (150 mL) wasadded PPTS (891 mg, 3.6 mmol), then dihydropyran (10.6 g, 0.126 mol) wasadded dropwise at 0° C. The mixture was stirred at room temperature for4 h. It was partitioned between DCM and water. The organic phase waswashed with brine, dried over sodium sulfate, filtered and concentratedto give a crude product which was purified by column chromatographyeluting with petroleum ether/ethyl acetate (50:1) to give2-(2-bromoethoxy)tetrahydro-2H-pyran(18.0 g, 72.0% yield) as a lightyellow oil.

Intermediate 3 2-(3-bromopropoxy)tetrahydro-2H-pyran

To a solution of 3-bromopropan-1-ol (8 g, 57.9 mmol) in DCM (100 mL) wasadded PPTS (891 mg, 3.6 mmol), then dihydropyran (7.3 g, 86.9 mmol) wasadded dropwise at 0° C. The mixture was stirred at room temperatureovernight. It was partitioned between DCM and water. The organic phasewas washed with brine, dried over sodium sulfate, filtered andconcentrated to give a crude product which was purified by columnchromatography eluting with petroleum ether/ethyl acetate (50:1) to give2-(3-bromopropoxy)tetrahydro-2H-pyran (8.9 g, 69.0% yield) as a lightyellow oil.

Intermediate 4 2-(chloromethyl)-5-methylthiazole

Step 1 (5-methylthiazol-2-yl)methanol

To a solution of n-BuLi (8.4 ml, 13.48 mmol) in THF (30 mL) was added2-bromo-5-methylthiazole(2.0 g, 11.23 mmol) dropwise under a nitrogenatmosphere at −70° C.; then it was stirred at this temperature for 1.5h. DMF (1.3 ml, 16.85 mmol) was added dropwise under nitrogen atmosphereat −70° C. The resulting mixture was stirred at this temperature for 1h. Then the mixture was quenched with aqueous saturated ammoniumchloride (5 mL), the mixture was partitioned between ethyl acetate andwater. The organic layers were combined, dried over sodium sulfate,filtered and concentrated to give a yellow oil. The yellow oil wasdissolved in methanol (15 ml), sodium borohydride (512 mg, 13.48 mmol)was added portionwise under a nitrogen atmosphere at −60° C. The mixturewas stirred at this temperature for 1 h. The reaction mixture wasquenched with acetone and concentrated. The residue was partitionedbetween ethyl acetate and water. The organic layers were dried oversodium sulfate, filtered and concentrated, then purified by silica gelchromatography eluting with petroleum/ethyl acetate=3:1 to givethiazol-2-ylmethanol (1.3 g, 90.3%) as brown oil. LCMS retention time0.366 min; LCMS MH⁺ 130.

Step 2 2-(chloromethyl)-5-methylthiazole

To a solution of (5-methylthiazol-2-yl)methanol (0.5 g, 3.87 mmol) inDCM (5 mL) was added thionyl chloride (0.19 ml, 2.6 mmol) at 0° C., thenthe mixture was stirred at room temperature for 2 h. The solvent wasconcentrated to give 2-(chloromethyl)-5-methylthiazole (570 mg) as ayellow oil which was used without purification. LCMS retention time0.912 min; LCMS MH⁺ 148.

Intermediate 5 2-(3-(trifluoromethoxy)phenoxy)ethanol

To a solution of 3-(trifluoromethoxy)phenol(3 g, 16.8 mmol) in DMF (30mL) was added 2-bromoethanol (3.16 g, 25.3 mmol), potassiumcarbonate(4.65 g, 33.7 mmol). The mixture was heated at 80° C.overnight. The mixture was cooled, partitioned between ethyl acetate andwater. The organic layers were combined, dried over sodium sulfate,filtered and concentrated to give a crude product which was purified bya column chromatography eluting with petroleum ether and ethylacetate(10:1) to give 2-(3-(trifluoromethoxy)phenoxy)ethanol (3.5 g,94.5% yield) as a yellow oil. ¹H-NMR (DMSO-d₆) δ 7.28-7.30 (t, 1H),6.81-6.86 (m, 2H), 6.78 (s, 1H), 4.07-4.09 (t, 2H), 3.95-3.99 (m, 2H),2.58 (t, 1H).

Intermediate 68-bromo-7-ethyl-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

Step 18-bromo-7-ethyl-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.4 g,1.32 mmol, product of intermediate 16 step 2) in DMF (10 mL) was addediodoethane (0.25 g, 1.58 mmol) and potassium carbonate (0.27 g, 1.98mmol). The reaction was heated at 50° C. for 2 h. The mixture was cooledand partitioned between ethyl acetate and water. The combined organiclayer was dried over sodium sulfate, filtered and concentrated to give8-bromo-7-ethyl-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.4 g, 91.7% yield) as white solid. LCMS retention time 1.674 min; LCMSMH⁺ 331.

Step 28-bromo-7-ethyl-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-ethyl-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.4g, 1.2 mmol) in DCM (10 mL) was added PPTS (27 mg, 0.1 mmol); thendihydropyran (0.15 g, 1.8 mmol) was added dropwise at 0° C. The mixturewas stirred at room temperature overnight. The mixture was partitionedbetween DCM and water. The organic phase was washed with brine, driedover sodium sulfate, filtered and concentrated to give a crude productwhich was purified by a column chromatography eluting with petroleumether/ethyl acetate (3:1) to give8-bromo-7-ethyl-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(0.38 g, 76.9% yield) as white solid. LCMS retention time 1.871 min;LCMS MH⁺-THP 331.

Intermediate 77-(4-chlorobenzyl)-8-mercapto-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(400 mg, 0.781 mmol, intermediate 14) in DMF (10 mL) was added sodiumsulfide nonahydrate (375 mg, 1.563 mmol). The reaction was stirred at85° C. for 16 h. The mixture was cooled, diluted with ethyl acetate andwater, and the phases were separated. The organic phase was washed withbrine, dried over sodium sulfate, filtered and concentrated to give7-(4-chlorobenzyl)-8-mercapto-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(230 mg, 63.4%) as orange oil. LCMS retention time 1.517 min; LCMSMH⁺-THP 381.

Intermediate 88-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 1 8-bromo-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of 3-methyl-1H-purine-2,6(3H,7H)-dione (11.3 g, 6.8 mmol)in acetic acid (300 mL) was added sodium acetate (8.37 g, 13.6 mmol)followed by drop-wise addition of bromine (13.04 g, 8.2 mmol) at 50° C.After addition, the mixture was stirred at 65° C. for 3 h. The mixturewas cooled and poured into ice-water (500 g), and the productprecipitated. The slurry was filtered and the filter cake was washedwith water twice and dried under vacuum to give8-bromo-3-methyl-1H-purine-2,6(3H,7H)-dione (16.1 g, 96.6% yield) aslight yellow solid. LCMS retention time 0.541 min; LCMS MH⁺ 245.

Step 2 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of 8-bromo-3-methyl-1H-purine-2,6(3H,7H)-dione (10.8 g,4.42 mmol) in DMF (200 mL) was added 1-(bromomethyl)-4-chlorobenzene (10g, 4.86 mmol) followed by potassium carbonate (9.16 g, 6.63 mmol). Theresulting mixture was stirred at 45° C. for 2 h. The mixture was dilutedwith ethyl acetate (300 mL) and washed with brine (200 mL). The layerswere separated and the organic slurry was filtered and the filter cakewas washed with ice cold ethanol, dried under vacuum to give8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (10.6 g,64.9% yield) as white solid. LCMS retention time 1.637 min; LCMS MH⁺369.

Intermediate 97-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of intermediate 12,step 2 to give7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(1.97 g, 80.1% yield) as white solid. LCMS retention time 1.724 min,LCMS MH⁺ 467.

Intermediate 108-chloro-7-(4-chlorobenzyl)-1-methyl-1H-purine-2,6(3H,7H)-dione

Step 1 6-amino-3-methylpyrimidine-2,4(1H,3H)-dione

To a solution of the 6-aminopyrimidine-2,4(1H,3H)-dione (15 g, 118 mmol)in 1,1,1,3,3,3-hexamethyldisilazane (50 mL) was added ammoniumsulfate(0.671 g, 5 mmol), then the resulting mixture was heated toreflux with stirring for 6 h. The mixture was concentrated to give alight-yellow solid. This solid was combined with acetonitrile (50 mL)and iodomethane (15 mL, 250 mmol) was added. The resulting mixture wasstirred at 40° C. for 16 h. Then the mixture was concentrated,neutralized with saturated sodium bicarbonate to pH=7, filtered, and thefilter cake was washed with brine and ethanol, dried under vacuum togive 6-amino-3-methylpyrimidine-2,4 (1H,3H)-dione (7.1 g, 42.6% yield)as yellow solid. LCMS MH⁺ 142.

Step 2 6-amino-3-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione

To a solution of 6-amino-3-methylpyrimidine-2,4(1H,3H)-dione (6 g, 42.6mmol) in acetic acid (50 mL) was added a solution of sodium nitrite (6.8g, 98.6 mmol) in water (20 mL) dropwise, then the mixture was stirred atroom temperature for 1 h. The mixture was filtered, the filter cake waswashed with water and ethanol and dried under vacuum to give6-amino-3-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione as violet solid,which was used directly in the next step.

Step 3 5,6-diamino-3-methylpyrimidine-2,4(1H,3H)-dione

To a solution of 6-amino-3-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dionein ammonium hydroxide

(100 mL) was added sodium hydrosulfite (6.8 g, 39.1 mmol) in smallportions at 70° C., the mixture was stirred at 70° C. for 1 h. Themixture was concentrated and ice-water was added. The slurry wasfiltered and the filter cake was washed with water and ethanol and driedunder vacuum to give 5,6-diamino-3-methylpyrimidine-2,4(1H,3H)-dione(2.0 g, 30.1% yield over two steps) as yellow solid. LCMS MH⁺ 157.

Step 46-amino-5-(4-chlorobenzylamino)-3-methylpyrimidine-2,4(1H,3H)-dione

To a solution of 5,6-diamino-3-methylpyrimidine-2,4(1H,3H)-dione (0.8 g,5.13 mmol) in water (10 mL) and acetic acid (0.5 mL) was added4-chlorobenzaldehyde(0.72 g, 5.14 mmol), the mixture was stirred at roomtemperature for 5 h. The mixture was cooled to 0° C., sodiumcyanoborohydride (0.3 g, 4.76 mmol) was added and the resulting mixturewas stirred at room temperature overnight. The mixture was concentratedand filtered, and the filter cake was washed with methanol, dried invacuo to give6-amino-5-(4-chlorobenzylamino)-3-methylpyrimidine-2,4(1H,3H)-dione (0.6g, 42.9% yield) as yellow solid. LCMS MH⁺ 281.

Step 56-amino-5-(4-chlorobenzylamino)-3-methylpyrimidine-2,4(1H,3H)-dione

To a solution of6-amino-5-(4-chlorobenzylamino)-3-methylpyrimidine-2,4(1H,3H)-dione(0.56 g, 2.0 mmol) in toluene (10 mL) was added trimethyl orthoformate(20 mL, 183 mmol), the mixture was stirred at 110° C. for 5 h. Then themixture was concentrated and filtered, the filter cake was washed withdiethyl ether and dried under vacuum to give6-amino-5-(4-chlorobenzylamino)-3-methylpyrimidine-2,4(1H,3H)-dione (0.5g, 86.2% yield) as light-yellow solid. Mass spec: 291(M+H).

Step 6 8-chloro-7-(4-chlorobenzyl)-1-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of6-amino-5-(4-chlorobenzylamino)-3-methylpyrimidine-2,4(1H,3H)-dione (0.5g, 1.72 mmol) in THF (20 ml) was added NCS (0.3 g, 2.26 mmol), themixture was stirred at room temperature for 16 h. Then the mixture wasconcentrated, diluted with ethyl acetate and water, and the phases wereseparated. The organic phase was washed with brine, dried over sodiumsulfate, filtered and concentrated to give product8-chloro-7-(4-chlorobenzyl)-1-methyl-1H-purine-2,6(3H,7H)-dione (500 mg,89.3% yield) as light yellow solid. LCMS MH⁺ 325.

Intermediate 118-bromo-7-(4-chlorobenzyl)-3-methyl-1-(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.2 g,0.54 mmol, intermediate 8) in DMF (3 mL) were added2-(2-bromoethoxy)tetrahydro-2H-pyran (169 mg, 0.81 mmol, intermediate1), potassium carbonate (150 mg, 1.08 mmol) and a catalytic amount ofTBAI. The mixture was stirred at 50° C. overnight. It was partitionedbetween ethyl acetate and water. The organic phase was washed withbrine, dried over sodium sulfate, filtered and concentrated to givecrude product, which was washed with ethanol and dried under vacuum togive8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-purine-2,6(3H,7H)-dione(260mg, 88.8%) as white solid. LCMS retention time 1.712 min, LCMS MH⁺-THP459.

Intermediate 121-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 18-bromo-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of 8-bromo-3-methyl-1H-purine-2,6(3H,7H)-dione (3.5 g,14.3 mmol, intermediate 8 step 1) in DMF (30 mL) was added potassiumcarbonate (3.9 g, 28.6 mmol). Then 2-(trimethylsilyl)ethoxymethylchloride (2.37 g, 14.3 mmol) was added dropwise 0° C., it was stirredroom temperature for 3 h. The mixture was partitioned between ethylacetate and water. The organic layers were combined, dried over sodiumsulfate, filtered and concentrated to give a crude product which waswashed with ethanol and dried in vacuo to give8-bromo-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(4.0 g, 74.9%) as a white solid. LCMS retention time 1.458 min, LCMS MH⁺377.

Step 23-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(2.5 g, 6.65 mmol) in DMF (30 mL) were added 3-(trifluoromethoxy)phenol(1.78 g, 9.97 mmol) and potassium carbonate (3.9 g, 28.6 mmol). It washeated at 80° C. overnight. The mixture was cooled, partitioned betweenethyl acetate and water. The organic layers were combined, dried oversodium sulfate, filtered and concentrated to give a crude product whichwas washed with ethanol and dried in vacuo to give3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(1.7 g, 54.3%) as a white solid. LCMS retention time 1.850 min, LCMS MH⁺473.

Step 33-methyl-1-(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(1.2 g, 2.54 mmol) in DMF (15 mL) were added2-(2-(2-chloroethoxy)ethoxy)tetrahydro-2H-pyran (0.79 g, 3.82 mmol,intermediate 1), potassium carbonate (0.7 g, 5.08 mmol), TBAI (2 mg,0.02 mmol). It was heated at 80° C. overnight. The mixture was cooled,partitioned between ethyl acetate and water. The organic layers werecombined, dried over sodium sulfate, filtered and concentrated to give acrude product (1.6 g, 98.1%) as a yellow oil which was used withoutpurification. LCMS retention time 2.179 min, LCMS MH⁺-THP 561.

Step 41-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of3-methyl-1-(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(0.64g, 1.16 mmol,) in ethanol (15 mL) was added HCl (3 mL); then it wasrefluxed overnight. The solvent was concentrated to give a crude productwhich was purified by a column chromatography to give1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(420 mg, 84% yield) as a white solid. LCMS retention time 1.209 min,LCMS MH⁺ 431.

Intermediate 138-bromo-7-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (2.0 g,5.4 mmol, intermediate 8) in DMF (10 mL) was added2-(2-bromoethoxy)tetrahydro-2H-pyran (1.35 g, 6.5 mmol, intermediate 2),potassium carbonate (1.49 g, 10.8 mmol). The mixture was stirred at 50°C. overnight. It was partitioned between ethyl acetate and water. Theorganic phase was washed with brine, dried over sodium sulfate, filteredand concentrated to give a crude product which was washed with ethanoland dried under vacuum to give8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-purine-2,6(3H,7H)-dione(2.10 g, 74.4%) as a white solid. LCMS retention time 1.669 min LCMSMH⁺-THP 415.

Intermediate 148-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.5 g,1.35 mmol, intermediate 8) in DMF (5 mL) was added2-(3-bromopropoxy)tetrahydro-2H-pyran(0.45 g, 2.03 mmol, intermediate3), potassium carbonate (0.37 g, 2.7 mmol). The mixture was stirred at50° C. for 3 h; then it was partitioned between ethyl acetate and water.The organic phase was washed with brine, dried over sodium sulfate,filtered and concentrated to give a crude product which was washed withethanol and dried under vacuum to give8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(0.5g, 72.2%) as a white solid. LCMS retention time 1.732 min, LCMS MH⁺-THP429.

Intermediate 151-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 13-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(1.0 g, 2.12 mmol, intermediate 12, step 2) in DMF (10 mL) was added2-(3-bromopropoxy)tetrahydro-2H-pyran (0.57 g, 2.54 mmol, intermediate3) and potassium carbonate (0.88 g, 6.36 mmol). The reaction was heatedat 50° C. for 3 h. The mixture was cooled, partitioned between ethylacetate and water. The organic layers were combined, dried over sodiumsulfate, filtered and concentrated to give a crude product which waspurified by column chromatography eluting with petroleum ether/ethylacetate (1:3) to give3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(0.9 g, 70.0% yield) as a white solid. LCMS retention time 2.270 min,LCMS MH⁺-THP 531.

Step 21-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(0.9 g, 1.5 mmol) in ethanol (10 mL) was added HCl (2 mL), then it wasrefluxed overnight. The solvent was concentrated to give a crude productwhich was collected, washed with ethanol and dried in vacuo to give1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.5 g, 80% yield) as a white solid. ¹H-NMR (DMSO-d6) δ 13.52 (br, 1H),7.55-7.59 (t, 1H), 7.47 (s, 1H), 7.36-7.38 (d, 1H), 7.28-7.30 (d, 1H),4.45 (br, 1H), 3.89-3.93 (t, 2H), 3.39-3.43 (t, 2H), 3.42 (s, 3H),1.66-1.69 (m, 2H). LCMS retention time 1.308 min, LCMS MH⁺ 401.

Intermediate 168-bromo-1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

Step 1 8-bromo-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-7-((2(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(4.0g, 10.6 mmol, intermediate 12 step 1) in DMF (50 mL) was added2-(3-bromopropoxy)tetrahydro-2H-pyran (2.6 g, 11.6 mmol, intermediate3), potassium carbonate (2.4 g, 17.4 mmol). It was heated at 60° C.overnight. The mixture was cooled, partitioned between ethyl acetate andwater. The organic layers were combined, dried over sodium sulfate,filtered and concentrated to give a crude product (5.2 g, 94.5%) as ayellow oil which was used directly for the next step had LCMS MH⁺ 518.

Step 2 8-bromo-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-7-((2(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (4.2 g, 8.12mmol) in ethanol (30 mL) was added HCl (6 mL). The mixture was refluxedovernight. The solvent was removed to give a crude product which waswashed with ethanol and dried in vacuo to8-bromo-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(2.0 mg,81.3% yield) as a white solid. LCMS MH⁺ 303.

Step 38-bromo-1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.5 g,1.65 mmol) in DMF (50 mL) was added 2-(chloromethyl)-5-methylthiazole(0.27 g, 1.81 mmol, intermediate 4), potassium carbonate (0.34 g, 2.48mmol) and TBAI (2 mg, 0.02 mmol). The mixture was heated at 60° C. for 3h. The mixture was cooled; then partitioned between ethyl acetate andwater. The organic layers were combined, dried over sodium sulfate,filtered and concentrated. The residue was purified by a columnchromatography eluting with DCM/methanol(60:1 to 30:1) to give8-bromo-1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione(0.4 g, 58.4%) as a yellow oil which was used without furtherpurification. LCMS MH⁺ 416.

Intermediate 173-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

Step 13-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of 2-(3-(trifluoromethoxy)phenoxy)ethanol (0.64 g, 2.9mmol, intermediate 5) in THF (15 mL) was added sodium hydride (0.23 g,9.67 mmol) at 0° C. it was stirred at 0° C. for 30 min, then8-bromo-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(1.0 g, 1.93 mmol, intermediate 16 step 1) was added. The mixture wasstirred 16 h. The reaction was quenched with aq. ammonium chloride (2mL) at 0° C.; then it was partitioned between ethyl acetate and water.The organic phases were combined, dried over sodium sulfate, filteredand concentrated to give a crude product which was used withoutpurification. LCMS retention time 2.144; LCMS MH⁺-THP 575.

Step 23-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(1.2 g, 1.82 mmol) in THF (15 mL) was added TBAF (3.7 mL, 3.64 mmol).The mixture was stirred at 80° C. overnight. Then it was cooled,partitioned between ethyl acetate and water. The organic layers werecombined, washed with water, dried over sodium sulfate, filtered andconcentrated to give a crude product which was purified by columnchromatography eluting with petroleum ether and ethyl acetate(2:1) togive3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione(900mg, 93.7% yield) as a white solid. LCMS retention time 1.613; LCMSMH⁺-THP 445.

Intermediate 187-benzyl-8-chloro-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

Step 1 2-amino-7-benzyl-1H-purin-6(7H)-one

To a solution of2-amino-9-((2R,3S,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one(14 g, 49.47 mmol) in DMSO (50 mL) was added (bromomethyl)benzene (10 g,59.36 mmol). The mixture was stirred at 50° C. overnight. Then themixture was cooled to room temperature and HCl (50 mL, 10% w.w) wasadded and the mixture was stirred at 70° C. for 2 h. The reaction wascooled to room temperature, filtered and the filter cake was washed withwater and ethanol and dried under vacuum to give2-amino-7-benzyl-1H-purin-6(7H)-one (10 g, 74.2% yield) as grey solid.LCMS retention time 0.529 min; LCMS MH⁺ 242.

Step 2 2-amino-7-benzyl-1H-purin-6(7H)-one

To a solution of 2-amino-7-benzyl-1H-purin-6(7H)-one (6.8 g, 28.33 mmol)in acetic acid (80 mL) and water (10 mL) was added a solution of sodiumnitrite (1.95 g, 28.26 mmol) in water (10 mL) at 50° C. dropwise, themixture was stirred at 50° C. for 1 h. Then the mixture was cooled toroom temperature and stirred for another 1.5 h. The mixture wasfiltered; then the filter cake was washed with water and ethanol, driedin vacuo to give 2-amino-7-benzyl-1H-purin-6(7H)-one (6.5 g, 94.9%yield) as yellow solid. LCMS retention time 0.502 min; LCMS MH⁺ 243.

Step 37-benzyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of 2-amino-7-benzyl-1H-purin-6(7H)-one (6.5 g, 26.86 mmol)in DMF (50 mL) was added potassium carbonate (5.6 g, 40.58 mmol),followed by 2-(trimethylsilyl)ethoxymethyl chloride (4.45 g, 27.08 mmol)at 0° C. The resulting mixture was stirred at 60° C. for 16 h. Themixture was diluted with water and filtered. The filter cake was washedwith water twice, dried in vacuo to give7-benzyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(10.8 g, 100% yield) as yellow oil. LCMS retention time 1.523 min; LCMSMH⁺-58 315.

Step 47-benzyl-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-benzyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(6.0 g, 16.13 mmol) in DMF (50 mL) was added NCS (3.23 g, 24.19 mmol)and the resulting mixture was stirred at room temperature for 8 h. Themixture was diluted with ethyl acetate and water, and the phases wereseparated. The organic phase was washed with brine, dried over sodiumsulfate, filtered and concentrated to give7-benzyl-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(5.1 g, 77.9% yield) as light yellow oil. Product tlc [petroleumether/ethyl acetate (15:1) iodine detection, Rf 0.6)

Step 57-benzyl-8-chloro-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-benzyl-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(5 g, 12.32 mmol) in DMF (30 mL) was added2-(3-bromopropoxy)tetrahydro-2H-pyran (3.60 g, 16.22 mmol, intermediate14 step 1), followed by potassium carbonate (3.4 g, 24.64 mmol). Themixture was stirred at 65° C. overnight. The mixture was diluted withethyl acetate and water, and the phases were separated. The organicphase was washed with brine, dried over sodium sulfate, filtered andconcentrated to give7-benzyl-8-chloro-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(6.3 g, 93.3% yield) as yellow oil. LCMS retention time 3.574 min; LCMSMNa⁺ 571.

Intermediate 19 1-(4-(bromomethyl)phenyl)ethanone

To a solution of 1-p-tolylethanone (600 mg, 4.47 mmol) in carbontetrachloride (15 mL) was added N-bromosuccinimide (955 mg, 5.37 mmol)and BPO (31 mg, 0.13 mmol). The mixture was refluxed for 3 h; then itwas cooled, and filtered. The filtrate was concentrated to give1-(4-(bromomethyl)phenyl)ethanone (683 mg, 71%) as a brown oil. LCMS MH⁺213.

Intermediate 20 2-(3-(4-methyloxazol-2-yl)phenyl)acetic acid

Step 1 2-(3-(4-methyloxazol-2-yl)phenyl)acetonitrile

A solution of 3-(cyanomethyl)benzamide (200 mg, 1.25 mmol) in1-chloropropan-2-one (2 mL) was microwave irradiated at 120° C. for 20min in a sealed tube. The mixture was concentrated to give crude product(110 mg), which was directly used to the next reaction withoutpurification. LCMS MH⁺ 199.

Step 2 2-(3-(4-methyloxazol-2-yl)phenyl)acetic acid

To a solution of 2-(3-(4-methyloxazol-2-yl)phenyl)acetonitrile (110 mg,0.555 mmol) in 1,4-dioxane (3 mL) was added 6N HCl (1 mL). Then themixture was stirred at 80° C. for 2 h. The mixture was concentrated andpurified via silica gel chromatography eluted with DCM/methanol (20:1)to give 2-(3-(4-methyloxazol-2-yl)phenyl)acetic acid (85 mg, 70.5%) asyellow syrup. LCMS retention time 0.920 min, LCMS MH⁺ 218.

Intermediate 21 1-(4-chlorophenyl)ethyl methanesulfonate

The title compound was prepared using the method of intermediate 34 togive 1-(4-chlorophenyl)ethyl methanesulfonate (258 mg, 23.6% yield) asyellow oil, which was directly used to the next reaction withoutpurification.

Intermediate 22 2-(bromomethyl)-5-methylthiazole

To a solution of 2,5-dimethylthiazole (200 mg, 1.77 mmol) in carbontetrachloride (5 mL) was added NBS (377 mg, 2.12 mmol), followed by BPO(20 mg, 0.083 mmol). Then the mixture was heated to reflux for 4 h withstirring. The mixture was cooled to room temperature and filtered, thefiltrate was concentrated to give crude product2-(bromomethyl)-5-methylthiazole (260 mg, 76.9%) as yellow oil, whichwas used without purification.

Intermediate 23 2-(chloromethyl)thiazole Step 1 thiazol-2-ylmethanol

To a solution of n-BuLi (8.4 ml, 1.6 mol/l, 13.4 mmol) in THF (30 mL)was added 2-bromothiazole (377 mg, 2.12 mmol) dropwise under nitrogenatmosphere at −70° C., and the mixture was stirred at the temperaturefor 1 h. Then DMF (1.4 ml, 18.3 mmol) was added into the solutiondropwise under nitrogen atmosphere at −70° C. The resulting mixture wasstirred at the temperature for 1 h. Then the mixture was quenched withaqueous saturated ammonium chloride, diluted with ethyl acetate andwater, and the phases were separated. The organic phase was washed withbrine, dried over sodium sulfate, filtered and concentrated to giveyellow oil. The yellow oil was dissolved in methanol (15 ml), cooled to−60° C., and sodium borohydride (463 mg, 12.2 mmol) was addedportionwise under nitrogen atmosphere. The mixture was stirred at thetemperature for 1 h. The reaction was quenched with acetone andconcentrated. The residue was diluted with ethyl acetate and water, andthe phases were separated. The organic layer was dried over sodiumsulfate, filtered and concentrated, then purified by silica gelchromatography eluting with petroleum/ethyl acetate=3:1 to givethiazol-2-ylmethanol (230 mg, 16.4% yield) as brown oil. LCMS MH⁺ 116.

Step 2 2-(chloromethyl)thiazole

To a solution of thiazol-2-ylmethanol (230 mg, 2.0 mmol) in DCM (5 mL)was added thionyl chloride (0.19 ml, 2.6 mmol) at 0° C. and the mixturewas stirred at room temperature for 1 h. The mixture was diluted withDCM and water, and the phases were separated. The organic layer wasdried over sodium sulfate, filtered and concentrated to give2-(chloromethyl)thiazole (240 mg, crude), which was used withoutpurification.

Intermediate 24 5-(chloromethyl)-2-methylpyrimidine Step 1(2-methylpyrimidin-5-yl)methanol

To a solution of 2-methylpyrimidine-5-carboxylic acid (150 mg, 1.23mmol) in ethanol (5 mL) was added sodium borohydride(93 mg, 2.46 mmol).The mixture was stirred at room temperature for 3 h. It was quenchedwith aqueous HCl (2 N, 2 mL), extracted with DCM, dried over sodiumsulfate, filtered and concentrated give the yellow oil product(2-methylpyrimidin-5-yl)methanol (95 mg, 62.6%). LCMS MH⁺ 125.

Step 2 5-(chloromethyl)-2-methylpyrimidine

A solution of (2-methylpyrimidin-5-yl)methanol (95 mg, 0.77 mmol) inthionyl chloride(1 mL) was stirred at room temperature for 1 h. Themixture was concentrated to dryness and used without purification. LCMSMH⁺ 143.

Intermediate 25 3-(4-methyloxazol-2-yl)phenol

Step 1 2-(3-methoxyphenyl)-4-methyloxazole

To a solution of 3-methoxybenzamide (1.5 g, 9.9 mmol) in toluene (15 mL)was added 1-chloropropan-2-one (1.37 g, 14.9 mmol), and the mixture wasstirred at reflux for 16 h. The mixture was cooled and concentrated togive crude product, which was purified via silica gel chromatographyeluted with ethyl acetate/petroleum ether (1:5) to give2-(3-methoxyphenyl)-4-methyloxazole (1.21 g, 64.6% yield) as yellowsyrup. LCMS MH⁺ 190.

Step 2 3-(4-methyloxazol-2-yl)phenol

A solution of 2-(3-methoxyphenyl)-4-methyloxazole (1.1 g, 5.79 mmol) inaqueous hydrogen bromide (10 mL, 48% w/w) was heated to 100° C. for 16h. The mixture was concentrated to give 3-(4-methyloxazol-2-yl)phenol(0.97 g, crude), which was used without purification. LCMS MH⁺ 176.

Intermediate 268-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione

Step 1 7-benzyl-8-chloro-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-benzyl-8-chloro-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(500 mg, 0.912 mmol, intermediate 18) in ethyl alcohol (20 mL) was addedconcentrated HCl (5 mL). The mixture was stirred at 80° C. overnight.Then the mixture was concentrated, neutralized with saturated sodiumbicarbonate and extracted with ethyl acetate. The organic phase waswashed with brine, dried over sodium sulfate, filtered and concentratedto give 7-benzyl-8-chloro-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione(280 mg, 91.9% yield) as yellow oil. LCMS retention time 1.710 min; LCMSMH⁺ 335.

Step 27-benzyl-8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-benzyl-8-chloro-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (150mg, 0.449 mmol) in DMF (5 mL) was added iodoethane (0.16 g, 0.13 mmol),followed by potassium carbonate (0.4 g, 2.90 mmol). The mixture wasstirred at 40° C. for 4 h. The reaction was cooled and diluted withethyl acetate. The organic phase was washed with water and brine; thenit was dried over sodium sulfate, filtered and concentrated to give7-benzyl-8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione(0.15 g, 92.3% yield) as yellow oil. LCMS retention time 1.296 min; LCMSMH⁺ 363.

Step 37-benzyl-8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione

A solution of sodium (50 mg, 2.17 mmol) in ethyl alcohol (10 mL) wasstirred at 40° C. under nitrogen until the sodium was consumed. Then7-benzyl-8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione(150 mg, 0.414 mmol) was added at 0° C. and the mixture was stirred at40° C. for 4 h. The mixture was quenched with ice-water (15 mL) andconcentrated. The aqueous residue was extracted with ethyl acetate. Theorganic phase was dried over sodium sulfate, filtered and concentratedto give7-benzyl-8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione(120 mg, 77.9% yield) as yellow solid. LCMS retention time 1.488 min;LCMS MH⁺ 373.

Step 4 8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione

7-benzyl-8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione(0.12 g, 0.323 mmol) was dissolved in ethanol (20 mL) and the mixturewas degassed and refilled with nitrogen three times. Ammonium formate(0.5 g, 7.94 mmol) and 10% Pd/C (30 mg) were added. The mixture wasagain degassed and refilled with nitrogen three times; then it waswarmed to 80° C. and stirred overnight. The mixture was cooled andfiltered, and the filter cake was washed with methanol. The filtrate wasconcentrated to give8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (70 mg,77.1% yield) as white solid. LCMS retention time 0.413 min; LCMS MH⁺283.

Intermediate 27 3-(morpholinomethyl)phenol

To a solution of 3-hydroxybenzaldehyde (1 g, 8.19 mmol) in methanol (15mL) was added morpholine (1.42 g, 16.4 mmol). Then the mixture wasstirred at room temperature for 1 h. The mixture was cooled to −5° C.,and sodium borohydride (403 mg, 10.6 mmol) was added in small portions.The resulting mixture was stirred at room temperature for 4 h. Themixture was quenched with diluted hydrochloride acid and concentrated.The aqueous solution was washed with ethyl acetate and then made basicby addition of ammonium hydroxide. The basic aqueous slurry wasextracted with ethyl acetate and this organic layer was dried andconcentrated to give 3-(morpholinomethyl)phenol (0.76 g, 48.2%) as whitesolid. LCMS retention time 0.871 min, LCMS MH⁺ 194.

Intermediate 28a and 28b 2-chloro-5-hydroxybenzaldehyde (28a) and4-chloro-3-hydroxybenzaldehyde (28b)

To a solution of 3-hydroxybenzaldehyde (1 g, 10 mmol) in acetonitrile(50 mL) was added p-toluenesulfonic acid (3.4 g, 20 mmol) portionwise.The mixture was stirred at room temperature for 5 min, and NCS (1.33 g,10 mmol) was added and the resulting mixture was stirred at roomtemperature for 2 h. The mixture was quenched with aqueous sodiumthiosulfate, and diluted with ethyl acetate and brine. The organic layerwas separated, dried, and concentrated to give the crude products whichwere purified by silica gel chromatography eluting with petroleumether/ethyl acetate (10:1 to 5:1) to give 2-chloro-5-hydroxybenzaldehyde(340 mg, 21.7% yield intermediate 28a) as yellow solid; ¹H-NMR (CDCl₃) δ10.43 (s, 1H), 7.54-7.56 (d, 1H), 7.30-7.37 (m, 2H) and4-chloro-3-hydroxybenzaldehyde (310 mg, 19.7% yield, intermediate 28b)as yellow solid. ¹H-NMR (CDCl₃) δ 10.43 (s, 1H), 7.40 (d, 1H), 7.33 (d,1H), 7.06-7.09 (dd, 1H).

Intermediate 29 4-chloro-3-(morpholinomethyl)phenol

To a mixture of 2-chloro-5-hydroxybenzaldehyde (200 mg, 1.27 mmol,intermediate 28a) and morpholine (280 mg, 3.21 mmol) in methanol (10 mL)was added 2 drops of acetic acid and the mixture was stirred at roomtemperature for 2 h. To the mixture, sodium borohydride (97 mg, 2.56mmol) was added and the resulting mixture was stirred at roomtemperature for 4 h. The mixture was quenched with dilute hydrochlorideacid and concentrated to give crude product. This crude material waspurified by silica gel chromatography eluting with petroleum ether/ethylacetate (5:1 to 1:1) to give 4-chloro-3-(morpholinomethyl)phenol (150mg, 51.8% yield) as white solid. LCMS retention time 0.378; LCMS MH⁺228.

Intermediate 30 4-chloro-3-(morpholinomethyl)phenol

The title compound was prepared using the method of intermediate 29starting with intermediate 28b but using sodium triacetoxyborohydride asthe reducing agent to give 4-chloro-3-(morpholinomethyl)phenol (190 mg,68.1% yield) as yellow solid. LCMS retention time 0.347; LCMS MH⁺ 228.

Intermediate 31 3-(chloromethyl)-5-methylisoxazole

Step 1 (5-methylisoxazol-3-yl)methanol

To a solution of ethyl 5-methylisoxazole-3-carboxylate (500 mg, 3.22mmol) in ethanol (8 mL) was added sodium borohydride (244 mg, 6.44 mmol)in portions at 0° C. After addition, the mixture was stirred at roomtemperature for 16 h. The mixture was quenched with dilutedhydrochloride acid. The mixture was extracted with ethyl acetate. Theorganic phase was washed with brine, dried and concentrated to give(5-methylisoxazol-3-yl)methanol (370 mg, 100% yield) as yellow oil,which was used directly in the next reaction without purification. LCMSretention time 0.391 min; LCMS MH⁺ 114.

Step 2 3-(chloromethyl)-5-methylisoxazole

To a solution of (5-methylisoxazol-3-yl)methanol (370 mg, 3.27 mmol) inDCM (5 mL) was added thionyl chloride (5 mL) dropwise. The resultingmixture was stirred at room temperature for 16 h. The mixture wasconcentrated to give 3-(chloromethyl)-5-methylisoxazole (350 mg, crude)as brown oil, which was used without purification. LCMS retention time0.768 min; LCMS MH⁺ 132.

Intermediate 32 2-(2-ethyl-1,3-dioxolan-2-yl)ethyl methanesulfonate

Step 1 methyl 2-(2-ethyl-1,3-dioxolan-2-yl)acetate

To a solution of methyl 3-oxopentanoate (3 g, 23.1 mmol) in toluene (30mL) was added ethane-1,2-diol (3 mL, 70.2 mmol) and p-toluenesulfonicacid (500 mg, 2.91 mmol), the resulting mixture was stirred at 120° C.overnight. Then the mixture was concentrated and partitioned betweenethyl acetate and aqueous saturated sodium bicarbonate solution. Thephases were separated and the aqueous layer was extracted with ethylacetate. The combined organic phase was washed with brine and dried oversodium sulfate; then it was filtered and concentrated to give methyl2-(2-ethyl-1,3-dioxolan-2-yl)acetate (1.7 g, 42.5%) as yellow oil whichwas used without purification. Product tlc [petroleum ether/ethylacetate (15:1) developed with iodine, Rf 0.6]

Step 2 2-(2-ethyl-1,3-dioxolan-2-yl)ethanol

To a solution of methyl 2-(2-ethyl-1,3-dioxolan-2-yl)acetate (1 g, 5.75mmol) in anhydrous THF (40 mL) was added LAH (900 mg, 23.7 mmol) at 0°C. under nitrogen atmosphere, the resulting mixture was stirred at 90°C. overnight. The mixture was cooled to room temperature, and ethylacetate was added to the mixture. The resulting slurry was filtered andthe filtrate was concentrated to dryness. The crude product was purifiedby silica gel chromatography eluting with DCM/methanol (100:1 to 20:1)to give 2-(2-ethyl-1,3-dioxolan-2-yl)ethanol (233 mg, 27.4%) as yellowoil that was used without purification.

Step 3 2-(2-ethyl-1,3-dioxolan-2-yl)ethyl methanesulfonate

To a solution of 2-(2-ethyl-1,3-dioxolan-2-yl)ethanol (233 mg, 1.59mmol) and TEA (327 mg, 3.2 mmol) in DCM (10 mL) was addedmethanesulfonyl chloride (0.23 ml, 2.92 mmol) at 0° C. The resultingmixture was stirred at room temperature for 3 h. The mixture was dilutedwith DCM and water, and the phases were separated. The organic phase waswashed with brine, dried over sodium sulfate, filtered and concentratedto give 2-(2-ethyl-1,3-dioxolan-2-yl)ethyl methanesulfonate (500 mg,100%) as yellow oil that was used without purification. Product tlc[DCM/methanol (100:1) developed with potassium permanganate, Rf 0.6]

Intermediate 33 3-hydroxybutyl 4-methylbenzenesulfonate

To a solution of butane-1,3-diol (1 g, 11.1 mmol), TEA (4.6 mL, 33.2mmol) and DMAP (30 mg, 0.25 mmol) in DCM (20 mL) was addedp-toluenesulfonyl chloride (2.75 g, 14.4 mmol) at 0° C. The resultingmixture was stirred at room temperature for 16 h. The mixture wasdiluted with DCM and water, and the phases were separated. The organicphase was washed with brine, dried over sodium sulfate, filtered andconcentrated to give 3-hydroxybutyl 4-methylbenzenesulfonate (3 g, 100%yield) as yellow oil, which was used without purification. Product tlc[DCM/methanol (100:1) developed with potassium permanganate, Rf 0.4]

Intermediate 34 2-(2-methoxyethoxy)ethyl methanesulfonate

To a solution of 2-(2-methoxyethoxy)ethanol (300 mg, 2.5 mmol) in DCM (5mL) was added methanesulfonyl chloride (370 mg, 2.6 mmol) dropwise at 0°C. After stirred at this temperature for 5 min, TEA (505 mg, 5.0 mmol)was added. It was stirred at room temperature overnight. The mixture waspartitioned between DCM and water. The organic layers were combined,dried over sodium sulfate, filtered and concentrated to give a crude oilproduct, which was used without purification. Product tlc [petroleumether/ethyl acetate [1:1) developed with iodine, Rf 0.5]

Intermediate 35 3-(3-(trifluoromethoxy)phenoxy)propan-1-ol

To a solution of 3-(trifluoromethoxy)phenol (0.3 g, 1.68 mmol) in DMF(10 mL) was added 3-bromopropan-1-ol (0.47 g, 3.37 mmol) and potassiumcarbonate (0.47 g, 3.37 mmol). The reaction was heated at 80° C.overnight. The mixture was cooled and partitioned between ethyl acetateand water. The organic layer was dried over sodium sulfate, filtered andconcentrated to give a crude product which was purified by columnchromatography eluting with petroleum ether and ethyl acetate(10:1) togive 3-(3-(trifluoromethoxy)phenoxy)propan-1-ol (0.32 g, 80.6% yield) asyellow oil.

Intermediate 36 3-(2-hydroxyethoxy)benzaldehyde

The title compound was prepared using the method of intermediate 5except the reaction was carried out at 140° C. to give3-(2-hydroxyethoxy)benzaldehyde (1.1 g, 73.4% yield) as yellow oil whichwas used without purification. ¹H-NMR (DMSO-d₆) δ 9.98 (s, 1H),7.53-7.51 (m, 2H), 7.44-7.43 (m, 1H), 7.30-7.29 (m, 1H), 4.95-4.93 (t,1H), 4.08-4.06 (t, 2H), 3.77-3.73 (q, 2H)

Intermediate 37 3-(3-(trifluoromethoxy)phenyl)propan-1-ol

Step 1 3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1-ol

To a solution of 1-iodo-3-(trifluoromethoxy)benzene (0.5 g, 1.73 mmol)in toluene (10 mL) was added prop-2-yn-1-ol (0.15 g, 2.62 mmol) andmorpholine (0.5 mL). Then cuprous iodide (4 mg, 0.02 mmol) andbis(triphenylphosphine)palladium(II) chloride (14 mg, 0.02 mmol) wereadded to the mixture under nitrogen. The reaction was heated at 80° C.overnight. The mixture was cooled and partitioned between ethyl acetateand water. The combined organic layer was dried over sodium sulfate,filtered and concentrated to give a crude product which was purified bycolumn chromatography eluting with ethyl acetate/petroleum ether (1:6 to1:3) to give 3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1-ol (0.3 g, 80.2%)as a yellow oil. LCMS retention time 1.552 min.

Step 2 3-(3-(trifluoromethoxy)phenyl)propan-1-ol

To a solution of 3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1-ol (0.3 g,1.39 mmol) in THF (10 mL) was added LAH (63 mg, 1.68 mmol) portionwiseat 0° C. The reaction was stirred at 0° C. for 3 h. The reaction wascarefully quenched by dropwise addition of ethyl acetate at 0° C. andthe mixture was partitioned between ethyl acetate and water. Thecombined organic layer was dried over sodium sulfate, filtered andconcentrated to give a crude product which was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:4 to 1:1)to give 3-(3-(trifluoromethoxy)phenyl)propan-1-ol (0.26 g, 85.2%) as ayellow oil which was used without purification. ¹H-NMR (CD₃OD) δ7.37-7.39 (d, 1H), 7.31-7.35 (m, 1H), 7.15-7.17 (d, 1H), 4.07-4.11 (t,2H), 2.72-2.76 (t, 2H), 1.83-1.90 (m, 2H).

Intermediate 38 2-(cyclohexyloxy)ethanol

Step 1 1,4-dioxaspiro[4.5]decane (JF-000357-022)

To a solution of cyclohexanone (10 g, 0.102 mol) in ethylene glycol (50mL) was added iodine (3.88 g, 15.3 mmol) and the resulting mixture wasstirred at room temperature overnight. The mixture was diluted withethyl acetate and extracted with saturated aqueous sodium thiosulfate.The organic phase was dried and concentrated to give a crude product,which was purified via silica gel chromatography eluting with ethylacetate/petroleum ether (1:8) to give 1,4-dioxaspiro[4.5]decane (6.8 g,46.9% yield) as light oil. ¹H-NMR (CDCl₃) δ 3.93 (s, 4H), 1.58-1.59 (d,8H), 1.39-1.41 (m, 2H).

Step 2 2-(cyclohexyloxy)ethanol

To the slurry of zirconium tetrachloride (10.65 g, 45.7 mmol) in THF(100 mL) was added sodium borohydride (4.3 g, 114.3 mmol) in smallportions at room temperature. A solution of 1,4-dioxaspiro[4.5]decane(6.5 g, 45.7 mmol) in THF (20 mL) was added dropwise and the resultingmixture was stirred at room temperature overnight. The reaction wascarefully quenched with 1N HCl and extracted with ethyl acetate. Theorganic phase was washed with brine, dried and concentrated to give acrude product, which was purified via silica gel chromatography elutingwith petroleum ether/ethyl acetate (3:2) to give2-(cyclohexyloxy)ethanol (3.9 g, 59.2% yield) as light yellow oil.¹H-NMR (CDCl₃) δ 3.68-3.70 (t, 2H), 3.53-3.56 (m, 2H), 3.27-3.29 (m,1H), 2.54 (br, 1H), 1.89-1.93 (m, 2H), 1.70-1.73 (m, 2H), 1.51-1.54 (m,1H), 1.17-1.28 (m, 5H).

Intermediate 397-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 18-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of5,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (80mg, 0.289 mmol, intermediate 59) in ethanol (2 mL) was added2-(2-fluoro-5-(trifluoromethoxy)phenyl)acetic acid (68.8 mg, 0.289 mmol)followed by EDCI (66.5 mg, 0.347 mmol) and the mixture was stirred atroom temperature for 2 h. The reaction was partitioned between ethylacetate and brine. The organic phase was dried and concentrated. Theresidue was dissolved in ethanol (3 mL) and 1 mM sodium hydroxide (1 mL)was added. The resulting mixture was stirred at reflux for 3 h. Thereaction was concentrated and residue was partitioned between ethylacetate and brine. The organic layer was dried and concentrated to givea crude solid product, which was triturated with ethanol, collected anddried to afford8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(67 mg, 48.4% yield) as a light yellow solid. LCMS retention time 1.611min; LCMS MH⁺ 479.

Step 27-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(67 mg, 0.14 mmol) in DMF (3 mL) was added1-(bromomethyl)-4-chlorobenzene (43.2 mg, 0.21 mmol) followed bypotassium carbonate (38.7 mg, 0.28 mmol). The reaction was heated to 60°C. for 3 h. The reaction was partitioned between ethyl acetate andbrine. The organic phase was dried and concentrated to give a crudeproduct, which was purified by silica gel chromatography eluting withDCM/methanol (60:1) to give7-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(71.2 mg, 84.3% yield) as a white solid. LCMS retention time 2.375 min;LCMS MH⁺ 603.

Step 37-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(71 mg, 0.118 mmol) in DCM (1 mL) was added TFA (0.3 mL) andtrifluoromethanesulfonic acid (0.2 mL). The reaction was stirred at roomtemperature for 16 h. The mixture was concentrated and the residue waspartitioned between DCM and aqueous sodium bicarbonate. The organiclayer was dried and concentrated to give7-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(39 mg, 68.4% yield) as a yellow syrup, which was directly withoutpurification. LCMS retention time 1.686 min; LCMS MH⁺ 483.

Intermediate 40 (5-methyloxazol-2-yl)methanol

Step 1 ethyl 2-(2-hydroxypropylamino)-2-oxoacetate

To a mixture of 1-aminopropan-2-ol (2 g, 26.6 mmol) and TEA (4.03 g,39.9 mmol) in DCM (50 mL) was added ethyl 2-chloro-2-oxoacetate (4.36 g,31.95 mmol) dropwise at 0° C. The mixture was stirred at roomtemperature for 16 h. The mixture was diluted with DCM and extractedwith brine. The organic layer was dried and concentrated to give a crudeproduct which was purified by silica gel chromatography eluting withpetroleum ether/ethyl acetate (2:1) to give ethyl2-(2-hydroxypropylamino)-2-oxoacetate (2.19 g, 51% yield) as yellowsyrup. LCMS retention time 0.348 min, LCMS MH⁺ 176.

Step 2 ethyl 2-oxo-2-(2-oxopropylamino)acetate

To a solution of ethyl 2-(2-hydroxypropylamino)-2-oxoacetate (2.1 g, 13mmol) in DCM (30 mL) was added Dess-Martin periodinane (6.2 g, 14.6mmol) in portions at 0° C. and the resulting mixture was stirred at roomtemperature for 16 h. The reaction was diluted with DCM and extractedwith saturated aqueous sodium bicarbonate solution and brine. Theorganic layer was dried and concentrated to give crude product, whichwas purified via silica gel chromatography eluting with DCM/methanol(60:1) to give ethyl 2-oxo-2-(2-oxopropylamino)acetate (1.7 g, 81.2%yield) as yellow syrup. LCMS retention time 0.392 min, LCMS MH⁺ 174.

Step 3 ethyl 5-methyloxazole-2-carboxylate

To a solution of ethyl 2-oxo-2-(2-oxopropylamino)acetate (1.7 g, 9.8mmol) in toluene (10 mL) was added phosphorus oxychloride (2 mL). Themixture was heated to reflux for 3 h. The reaction was concentrated todryness and the residue was taken up in ethyl acetate (20 mL). Thisorganic phase was washed with saturated aqueous sodium bicarbonatesolution and brine, dried and concentrated to give a crude product whichwas purified via silica gel chromatography eluting with petroleumether/ethyl acetate (4:1) to give ethyl 5-methyloxazole-2-carboxylate(0.68 g, 44.1% yield) as yellow syrup. ¹H-NMR (CDCl₃) δ 6.97 (s, 1H),4.44-4.49 (q, 2H), 2.43 (s, 3H), 1.42-1.46 (t, 2H). LCMS retention time0.643 min; LCMS MH⁺ 156.

Step 4 (5-methyloxazol-2-yl)methanol

To a solution of ethyl 5-methyloxazole-2-carboxylate (0.68 g, 4.38 mmol)in anhydrous THF (10 mL) was added LAH (250 mg, 6.59 mmol) in portionsat 0° C. The resulting mixture was stirred at room temperature for 16 h.The mixture was quenched with ethyl acetate and filtered. The filtercake was washed several times with ethyl acetate and the combinedfiltrate was concentrated to give crude product which was purified viasilica gel chromatography eluting with DCM/methanol (65:1) to give(5-methyloxazol-2-yl)methanol (0.33 g, 66.6% yield) as yellow syrup.LCMS retention time 0.328 min; LCMS MH⁺ 114.

Intermediate 41 5-(chloromethyl)isoxazole

To a solution of isoxazole-5-carboxylic acid (1.0 g, 8.8 mmol,) in THF(10 mL) was added borane-THF complex (26.4 mL, 26.4 mmol) at 0° C. Thereaction was stirred at room temperature until the substrate wasconsumed. The reaction was quenched with ethanol (5 mL) at 0° C. Thereaction mixture was partitioned between ethyl acetate and water. Thecombined organic phase was dried over sodium sulfate, filtered andconcentrated to give a crude product which was purified by columnchromatography eluting with petroleum ether/ethyl acetate (2:1 to giveisoxazol-5-ylmethanol (670 mg, 77.0% yield) as a light yellow oil. LCMSretention time 0.329 min; LCMS MH⁺ 100.

Isoxazol-5-ylmethanol (50 mg, 0.5 mmol,) was dissolved in thionylchloride (1 mL) at 0° C. The reaction was stirred at room temperatureuntil the substrate was consumed. The reaction was concentrated to give5-(chloromethyl)isoxazole as a brown solid which was used withoutpurification. LCMS retention time 0.349 min; LCMS MH⁺ 118.

Intermediate 42 (1-(hydroxymethyl)cyclopropyl)methyl methanesulfonate

To a solution of cyclopropane-1,1-diyldimethanol (0.1 g, 0.98 mmol) inDCM (5 mL) was added TEA (0.15 g, 1.44 mmol). Methanesulfonyl chloride(0.11 g, 0.98 mmol) was added dropwise at 0° C. The reaction was stirredat room temperature for 2 h. The mixture was partitioned between DCM andwater. The combined organic layer was dried over sodium sulfate,filtered and concentrated to give a crude product which was used withoutpurification.

Intermediate 43 2-(1-hydroxycyclopentyl)ethyl methanesulfonate

Step 1 tert-butyl 2-(1-hydroxycyclopentyl)acetate

To a solution of tert-butyl acetate (5.0 g, 42.8 mmol,) in THF (20 mL)was added lithium diisopropylamide (21.4 mL, 42.8 mmol) at −60° C. Afterstirred at −60° C. for 30 min, cyclopentanone(3.0 g, 35.7 mmol) wasadded at −60° C. The reaction was stirred 1 h; then it was quenched withaqueous ammonium chloride (5 mL) at −60° C. and the mixture was warmedto room temperature. The reaction was partitioned between ethyl acetateand water. The combined organic layer was dried over sodium sulfate,filtered and concentrated to give a crude product which was purified bycolumn chromatography eluting with petroleum ether/ethyl acetate (3:1)to give tert-butyl 2-(1-hydroxycyclopentyl)acetate (5.0 g, 70.1% yield)as a yellow oil.

Step 2 1-(2-hydroxyethyl)cyclopentanol

To a solution of tert-butyl 2-(1-hydroxycyclopentyl)acetate (0.5 g, 2.5mmol) in THF (10 mL) was added lithium aluminium hydride (0.28 g, 7.5mmol) portionwise at 0° C. The reaction was stirred at room temperatureovernight. The mixture was partitioned between ethyl acetate and water.The combined organic layer was dried over sodium sulfate, filtered andconcentrated to give a crude product which was purified by columnchromatography eluting with petroleum ether/ethyl acetate (1:1) to give1-(2-hydroxyethyl)cyclopentanol (0.33 g, 100%) as a yellow oil.

Step 3 2-(1-hydroxycyclopentyl)ethyl methanesulfonate

To a solution of 1-(2-hydroxyethyl)cyclopentanol (19 0 mg, 1.46 mmol) indry dichloromethane (2 mL) was added methanesulfonyl chloride (200.3 mg,1.75 mmol) dropwise at 0° C., followed by TEA (295 mg, 2.92 mmol). Thenthe mixture was stirred at room temperature 1 h. The mixture waspartitioned between ethyl acetate and water. The organic phase waswashed with brine, dried over sodium sulfate, filtered and concentratedto give crude product (50 mg, 31.1% yield), which was used withoutpurification.

Intermediate 44 2-(1-hydroxycyclobutyl)ethyl methanesulfonate

The title product was prepared using the method of intermediate 43.

Intermediate 45 4-bromo-2-methylbutan-2-ol

To a solution of methyl 3-bromopropanoate (0.2 g, 1.2 mmol,) in THF (5mL) was added methyl magnesium bromide (2.4 mL, 2.4 mmol) at 0° C. Themixture was stirred at this temperature until the substrate was consumedbased on tlc [petroleum ether/ethyl acetate (3:1); product Rf 0.3]. Thereaction was quenched with ammonium chloride (2 mL) at 0° C. The mixturewas partitioned between ethyl acetate and water. The combined organiclayer was dried over sodium sulfate, filtered and concentrated to give acrude product which was purified by a column chromatography eluting withpetroleum ether/ethyl acetate (3:1) to give 4-bromo-2-methylbutan-2-ol(0.15 g, 75.1% yield) as a yellow oil.

Intermediate 46 1-(2-bromoethyl)cyclopropanol

To a solution of ethyl 3-bromopropanoate (0.5 g, 2.76 mmol,) in THF (5mL) was added titanium tetra-isopropanolate (0.8 mL, 0.27 mmol) at 0° C.Ethyl magnesium bromide (8.27 mL, 8.27 mmol) was added to the mixture at0° C. The reaction was stirred at this temperature 2 h. The reaction wasquenched with aqueous ammonium chloride (2 mL) at 0° C. The mixture waspartitioned between ethyl acetate and water. The combined organic layerwas dried over sodium sulfate, filtered and concentrated to give a crudeproduct which was purified by column chromatography eluting withpetroleum ether/ethyl acetate (5:1) to give1-(2-bromoethyl)cyclopropanol (0.35 g, 77.7% yield) as a yellow oil.

Intermediate 477-benzyl-3-ethyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 17-benzyl-8-(3-(trifluoromethoxy)phenoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-benzyl-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(500 mg, 1.232 mmol, product of intermediate 18, step 4) in DMF (3 mL)was added 3-(trifluoromethoxy)phenol (280 mg, 1.55 mmol), followed bypotassium carbonate (400 mg, 2.90 mmol). The mixture was stirred at 80°C. overnight. The reaction was cooled and partitioned between ethylacetate and water. The organic phase was washed with brine, dried oversodium sulfate, and concentrated to give7-benzyl-8-(3-(trifluoromethoxy)phenoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(0.59 g, 87.3% yield) as brown oil. LCMS retention time 2.157 min; LCMSMH⁺ 549.

Step 27-benzyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-benzyl-8-(3-(trifluoromethoxy)phenoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(0.59 g, 1.07 mmol) in ethanol (20 mL) was added concentrated HCl (2mL). The reaction was stirred at 80° C. for 16 h. The reaction wasconcentrated and partitioned between ethyl acetate and saturated sodiumbicarbonate. The organic phase was washed with brine, dried over sodiumsulfate, and concentrated to give7-benzyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (390mg, 87.1% yield) as yellow oil. LCMS retention time 1.543 min; LCMS MH⁺419.

Step 37-benzyl-3-ethyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-benzyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (390mg, 0.93 mmol) in DMF (3 mL) was added iodoethane (150 mg, 0.962 mmol),followed by potassium carbonate (350 mg, 2.54 mmol). The reaction wasstirred at 40° C. for 2 h. The mixture was cooled and partitionedbetween ethyl acetate and water. The organic phase was washed withbrine, dried over sodium sulfate, and concentrated to give7-benzyl-3-ethyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(271 mg, 65.2% yield) as yellow solid. LCMS retention time 1.765 min;LCMS MH⁺ 447.

Step 4 8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione

7-benzyl-8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione(0.12 g, 0.323 mmol) was dissolved in ethanol (20 mL) and degassed andrefilled with nitrogen three times. Ammonium formate (0.5 g, 7.94 mmol)and 10% Pd/C (30 mg) were added and the mixture was again degassed andrefilled with nitrogen three times. The reaction was stirred at 80° C.overnight. Then the mixture was cooled, filtered and the filter cake waswashed with methanol. The filtrate was concentrated to give8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (70 mg,77.1% yield) as white solid. LCMS retention time 0.413 min; LCMS MH⁺283.

Intermediate 481-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione

Step 1N-(6-amino-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

To a solution of5,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (50mg, 0.181 mmol, intermediate 59) in ethanol (3 ml) was added2-(3-(trifluoromethoxy)phenyl)acetic acid (40 mg, 0.181 mmol) and EDCI(52 mg, 0.271 mmol) The mixture was stirred at room temperature for 2 h.The reaction was diluted with water, filtered and the solids were rinsedwith water. The solid residue was dissolved in ethyl acetate, dried oversodium sulfate, filtered and concentrated to giveN-(6-amino-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide(70 mg, 80.1%) as light gray solid. LCMS retention time 1.239 min; LCMSMH⁺ 479.

Step 21-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione

To a solution ofN-(6-amino-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide(70 mg, 0.146 mmol) in ethanol (7 ml) was added 2N sodium hydroxide (1ml). The reaction was stirred at 80° C. for 3 h. The reaction wasneutralized with aqueous ammonium chloride, filtered and the solids wererinsed with water. The solid residue was dissolved in ethyl acetate,dried over sodium sulfate, filtered and concentrated to give1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione(60 mg, 89.1%) as light yellow solid. LCMS retention time 1.499 min;LCMS MH⁺ 461.

Intermediate 49 3-(5-methylthiazol-2-yl)propanoic Acid

Step 1 (E)-ethyl 3-(5-methylthiazol-2-yl)acrylate

To a solution of n-BuLi (4.2 ml, 6.74 mmol) in THF (15 mL) was added2-bromo-5-methylthiazole (1.0 g, 5.65 mmol) dropwise under nitrogen at−70° C. The reaction was stirred at this temperature for 1.5 h. DMF(0.65 ml, 8.43 mmol) was added dropwise at −70° C. The reaction wasmaintained at this temperature 1 h. The reaction was quenched withaqueous saturated ammonium chloride (5 mL) and warmed to roomtemperature. The mixture was partitioned between ethyl acetate andwater. The combined organic layer was dried over sodium sulfate,filtered and concentrated to give the aldehyde intermediate as a yellowoil which was used without purification.

To a suspension of sodium hydride (0.27 g, 6.78 mmol) in THF (10 mL) wasadded ethyl 2-(diethoxyphosphoryl)acetate (1.52 g, 6.78 mmol) dropwiseat 0° C. After the reaction was stirred 30 min, a solution of thealdehyde in THF (3 mL) was added dropwise at 0° C. The reaction wasstirred at room temperature overnight. The mixture was quenched withaqueous saturated ammonium chloride (5 mL) and partitioned between ethylacetate and water. The combined organic layer was dried over sodiumsulfate, filtered and concentrated to give a yellow oil which waspurified by column chromatography eluting with petroleum ether/ethylacetate(4:1) to give (E)-ethyl 3-(5-methylthiazol-2-yl)acrylate (600 mg,54.1% yield) as a light yellow oil. LCMS retention time 1.410 min; LCMSMH⁺ 198.

Step 2 ethyl 3-(5-methylthiazol-2-yl)propanoate

To a solution of (E)-ethyl 3-(5-methylthiazol-2-yl)acrylate (200 mg,1.01 mmol,) in methanol (5 mL) was added 5% Pd/C (20 mg). The reactionwas purged with nitrogen and then hydrogen and then was stirred under ahydrogen atmosphere (balloon). The reaction was filtered. The filtratewas concentrated to give ethyl 3-(5-methylthiazol-2-yl)propanoate (200mg, 99% yield) as a light yellow oil. LCMS retention time 1.33 min; LCMSMH⁺ 200.

Step 3 3-(5-methylthiazol-2-yl)propanoic acid

To a solution of ethyl 3-(5-methylthiazol-2-yl)propanoate (0.2 g, 1mmol) in THF/water (3 mL/3 mL) was added lithium hydroxide (61 mg, 1.5mmol) portionwise at room temperature. The resulting mixture was stirredfor 3 h. The solvent was evaporated and the residue was acidified withconc. HCl to adjust the pH to 1-2. The mixture was partitioned betweenethyl acetate and water. The combined organic layer was dried oversodium sulfate and concentrated to afford3-(5-methylthiazol-2-yl)propanoic acid (0.17 g, 87.7% yield) as acolorless oil. LCMS retention time 0.436 min; LCMS MH⁺ 172.

Intermediate 50 2-(chloromethyl)-5-methylpyridine hydrochloride

Step 1 2,5-dimethylpyridine 1-oxide

To a solution of 2,5-dimethylpyridine (2.24 g, 21 mmol) in CHCl₃ (20 mL)was added MCPBA (4.31 g, 25 mmol) in portions over 30 min. The mixturewas stirred at room temperature overnight. Calcium hydroxide (4 g, 54mmol) was added to quench the reaction and the mixture was stirredvigorously for 3 h. The mixture was filtered through a Celite pad. Thefiltrate was concentrated and dried under vacuum to give 2,5-dimethylpyridine 1-oxide (2.5 g, 97.1% yield) as white solid, whichwas used without purification. CMS retention time 0.442 min; LCMS MH⁺124.

Step 2 (5-methylpyridin-2-yl)methanol

2, 5-Dimethylpyridine 1-oxide (2.5 g, 20.3 mmol) was added to aceticanhydride (8.2 mL) at 100° C. over a period of 30 min. Then the mixturewas refluxed 1 h. The mixture was cooled to room temperature andcarefully quenched with ethanol (11 mL). The reaction mixture wasconcentrated. The residue was treated with 1N HCl (6 mL) and refluxed 1h. The reaction was concentrated and the residue was partitioned betweenethyl acetate and water. The organic phase was dried over sodiumsulfate, filtered and concentrated to give (5-methylpyridin-2-yl)methanol (2 g, 80.0% yield) as a light yellow oil. LCMS MH⁺ 124.

Step 3 2-(chloromethyl)-5-methylpyridine hydrochloride

A solution of (5-methylpyridin-2-yl)methanol in SOCl₂ (10 mL) wasrefluxed 30 min. The mixture was concentrated and dried in vacuo to give2-(chloromethyl)-5-methylpyridine hydrochloride (2.1 g, 91.3% yield) aswhite solid. LCMS MH⁺ 142.

Intermediate 513-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione

Step 11-(4-methoxybenzyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione

To a solution of1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione(110 mg, 0.238 mmol, intermediate 48) in DMF (4 mL) was added2-(chloromethyl)-5-methylpyridine (33.8 mg, 0.238 mmol, intermediate50), followed by potassium carbonate (49.5 mg, 0.358 mmol). The reactionwas stirred at 55° C. for 2 h. The mixture was partitioned between ethylacetate and water. The organic phase was washed with brine, dried oversodium sulfate, filtered and concentrated to give a white solid product(120 mg, 88.8% yield) which was used without purification. LCMS MH⁺ 566.

Step 23-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione

To a solution of1-(4-methoxybenzyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (120 mg, 0.212 mmol) in DCM (1.4 mL)was added triflic acid (0.7 mL) and TFA (0.7 mL). The reaction wasstirred at room temperature overnight. The mixture was partitionedbetween ethyl acetate and water. The organic phase was washed withsaturated NaHCO₃ and brine, dried over sodium sulfate, filtered andconcentrated to give crude product, which was purified by silica gelchromatography eluting with petroleum/ethyl acetate (10:1 to 1:1) togive3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione(60 mg, 63.5% yield) as white solid. LCMS MH⁺ 446.

Intermediate 52 4,4,4-trifluorobutyl methanesulfonate

To a solution of 4,4,4-trifluorobutan-1-ol (100m g, 83 mmol) in dry DCM(2 mL) was added methanesulfonyl chloride (107.3 mg, 72 mmol) and thenby TEA (158 mg, 216 mmol) at 0° C. The reaction was stirred at roomtemperature for 1 h. The reaction was partitioned between ethyl acetateand water. The organic phase was washed with brine, dried over sodiumsulfate, filtered and concentrated to give a yellow oil product (50 mg,31.1% yield), which was used without purification. Product tlc[petroleum ether/ethyl acetate (3:1) Rf 0.4]

Intermediate 538-amino-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

Step 18-azido-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(0.28 g, 0.4 mmol, intermediate 14) in DMSO (10 mL) was added sodiumazide (65 mg, 1 mmol). The reaction was heated at 65° C. for 2.5 h. Themixture was cooled and partitioned between ethyl acetate and water. Thecombined organic layer was dried over sodium sulfate, filtered andconcentrated to give a crude product which was used withoutpurification. LCMS retention time 1.800 min; LCMS MH⁺-THP 390.

Step 28-amino-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

8-azido-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(0.19 g, 0.4 mmol) was dissolved in THF (5 mL) and 10% Pd/C (20 mg) wasadded. The reaction was blanketed in a hydrogen atmosphere (balloon) andstirred overnight at room temperature. The mixture was filtered throughcelite, the filter cake was washed with methanol. The filtrate wasconcentrated in vacuo to give a8-amino-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(0.2 g, 100% yield) as a white solid. LCMS retention time 1.324 min;LCMS MH⁺-THP 364

Intermediate 54 Synthesis of 2-(chloromethyl)-4-methylthiazole

Step 1 Synthesis of (4-methylthiazol-2-yl)methanol

To a solution of 4-methylthiazole (1.0 g, 10.1 mmol) in THF (30 mL) wasadded n-BuLi (7.56 mL, 13.48 mmol) dropwise under a nitrogen atmosphereat −60° C. The reaction was stirred for 1 h; then DMF (1.4 ml, 18.2mmol) was added dropwise while maintaining −60° C. The resulting mixturewas stirred at this temperature for 30 min. The reaction was quenchedwith aqueous saturated ammonium chloride (5 mL) and partitioned betweenethyl acetate and water. The combined organic layer was dried oversodium sulfate, filtered and concentrated to give a yellow oil. This oilwas dissolved in methanol (15 ml) and sodium borohydride (460 mg, 12.1mmol) was added portionwise under nitrogen atmosphere at −60° C. Themixture was stirred at this temperature for 1 h. The reaction mixturewas quenched with acetone, warmed to room temperature, and concentrated.The residue was partitioned between ethyl acetate and water. Thecombined organic layer was dried over sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatographyeluting with petroleum ether/ethyl acetate (3:1) to give(4-methylthiazol-2-yl)methanol (1.3 g, 90.3%) as brown oil. LCMSretention time 0.375 min; LCMS MH⁺ 130.

Step 2 Synthesis of 2-(chloromethyl)-4-methylthiazole

To a solution of (4-methylthiazol-2-yl)methanol (0.5 g, 3.87 mmol) inDCM (5 mL) was added thionyl chloride (0.19 ml, 2.6 mmol) at 0° C. Themixture was stirred at room temperature for 2 hour. The reaction wasconcentrated to give 2-(chloromethyl)-4-methylthiazole (570 mg, crude)as yellow oil, which was used without purification. LCMS retention time0.895 min; LCMS MH⁺ 148

Intermediate 55 2-(chloromethyl)-5-methylpyrazine

To a solution of 2,5-dimethylpyrazine (500 mg, 4.62 mmol) in carbontetrachloride (7 mL) was added NCS (679 mg, 5.09 mmol) followed by BPO(20 mg) and the mixture was heated to 80° C. for 6 hours. The mixturewas diluted with DCM and extracted with saturated aqueous sodium sulfitesolution and brine. The organic layer was dried and concentrated to givea crude product which was purified via silica gel chromatography elutingwith petroleum ether/ethyl acetate (1:0 to 15:1) to give2-(chloromethyl)-5-methylpyrazine (133 mg, 20.19% yield) as yellow oil.LCMS retention time 0.557 min; LCMS MH⁺ 143.

Intermediate 568-bromo-7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (150 mg,0.405 mmol, intermediate 8) in DMF (5 mL) was added1-(2-bromoethyl)cyclopropanol (94 mg, 0.568 mmol) followed by potassiumcarbonate (84 mg, 0.609 mmol) and TBAI (catalytic amount). The resultingmixture was stirred at 50° C. overnight. The reaction was diluted withethyl acetated and washed with brine. The organic phase was dried andconcentrated to give crude product which was purified via silica gelchromatography eluting with petroleum ether/ethyl acetate (5:1 to 2:1)to give8-bromo-7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(150 mg, 81.6% yield) as light yellow solid. LCMS retention time 1.523min; LCMS MH⁺ 455.

Intermediate 571-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 18-bromo-1-(3-hydroxybutyl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(3 g, 8 mmol, product of intermediate 12, step 1) in DMF (15 mL) wasadded 3-hydroxybutyl 4-methylbenzenesulfonate (2.3 g, 8.8 mmol,intermediate 33) followed by potassium carbonate (2.2 g, 16 mmol) andTBAI (catalytic amount). The resulting mixture was stirred at 80° C. for4 h. The reaction was diluted with ethyl acetated and washed with brine.The organic phase was dried and concentrated to give8-bromo-1-(3-hydroxybutyl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(3.5 g, 97.9% yield) as yellow solid. LCMS retention time 1.428 min;LCMS MH⁺ 448.

Step 31-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-1-(3-hydroxybutyl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(1 g, 2.2 mmol) in DNF (10 mL) was added 3-(trifluoromethoxy)phenol (0.6g, 3 mmol) followed by potassium carbonate (0.6 g, 4.4 mmol). Thereaction was stirred at 80° C. for 4 h. The mixture was diluted withethyl acetate and washed with brine. The organic phase was dried andconcentrated to give1-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(1.1 g, 91.8% yield) as yellow syrup. LCMS retention time 2.036 min;LCMS MH⁺ 545.

Step 3 Synthesis of1-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of1-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(1.1 g, 2.02 mmol) in THF (5 mL) was added TBAF (5 mL, 1 mmol/L in THF)and the mixture was heated at reflux for 16 h. The mixture was cooledand diluted with ethyl acetate. The organic phase was washed with brineand saturated aqueous ammonium chloride; then it was dried andconcentrated to give a crude product which was purified by silica gelchromatography eluting with DCM/methanol (45:1) to give (701 mg, 83.8%yield) as white solid. LCMS retention time 1.372 min; LCMS MH⁺ 415.

Intermediate 581-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of intermediate 57 andpurified by silica gel chromatography eluting with petroleum ether/ethylacetate (1:1) to give1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(400 mg, 87.0% yield) as white solid. LCMS retention time 1.457 min;LCMS MH⁺ 427.

Intermediate 595,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione

Step 1(E)-N′-(1-(4-methoxybenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide

To a solution of 6-amino-1-methylpyrimidine-2,4(1H,3H)-dione (13.1 g,92.9 mmol) in DMF (200 mL) was added1,1-dimethoxy-N,N-dimethylmethanamine (13 mL, 97.9 mmol) and the mixturewas stirred at 40° C. for 3 h. Then 1-(chloromethyl)-4-methoxybenzene(15.05 mL, 111.5 mmol) was added followed by potassium carbonate (25.64g, 0.186 mmol) and DMF (100 mL), the resulting mixture was stirred at80° C. for 48 h. The reaction was cooled and diluted with ethyl acetate.The organic phase was washed with brine, dried and concentrated to givea crude product which was purified by silica gel chromatography elutingwith methanol/DCM (1:80 to 1:20) to give(E)-N′-(1-(4-methoxybenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide(7.8 g, 26.5% yield) as yellow solid. LCMS retention time 1.023 min;LCMS MH⁺ 317.

Step 2 6-amino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione

To a solution of(E)-N′-(1-(4-methoxybenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide(7.8 g, 24.7 mmol) in methanol (90 mL) was added ammonium hydroxide (155mL, 28% wt/wt) and the mixture was stirred at room temperature for 48 h.The reaction was concentrated to give crude product which was purifiedby silica gel chromatography eluting with methanol/DCM (1:15) to give6-amino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (4.3 g,66.6%) as yellow solid. LCMS retention time 0.445 min; LCMS MH⁺ 262.

Step 36-amino-3-(4-methoxybenzyl)-1-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione

To a solution of6-amino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (4.3 g,16.45 mmol) in water (20 mL) and acetic acid (20 mL) was added sodiumnitrite (3.4 g, 49.4 mmol) in small portion at 70° C. After addition,the mixture was stirred at 70° C. for 4 h. The reaction was cooled andconcentrated. The solids were collected, washed with water and driedunder vacuum to give6-amino-3-(4-methoxybenzyl)-1-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione(4.1 g, 85.9% yield) as purple solid. LCMS retention time 0.885 min;LCMS MH⁺ 291.

Step 45,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione

To a solution of6-amino-3-(4-methoxybenzyl)-1-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione(4.1 g, 14.1 mmol) in ammonium hydroxide (100 mL, 14% wt/wt) was addedsodium dithionite (4.9 g, 28.2 mmol) in small portions at 60° C., andthe mixture was stirred at this temperature for 4 h. The reaction wascooled and was diluted with water. The solids were collected, rinsedwith water and dried under vacuum to give5,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (3.5g, 89.8% yield) as a light yellow solid. LCMS retention time 0.404 min;LCMS MH⁺ 277.

Intermediate 601-(4-methoxybenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione

Step 1 ethyl 3-(3-(trifluoromethoxy)phenoxy)propanoate

To a solution of ethyl 4-bromobutanoate (2 g, 10.26 mmol) in acetone (20mL) was added 3-(trifluoromethoxy)phenol (1.52 g, 8.54 mmol), followedby potassium carbonate (3.5 g, 25.36 mmol). The reaction was stirred atroom temperature overnight. The mixture was partitioned between DCM andwater. The organic phase was washed with brine, dried over sodiumsulfate, and concentrated to give a crude product which was purified bysilica gel chromatography eluting with petroleum/ethyl acetate (10:1 to5:1) to give ethyl 3-(3-(trifluoromethoxy)phenoxy)propanoate (2.3 g,92.1% yield) as a colorless oil.

Step 2 3-(3-(trifluoromethoxy)phenoxy)propanoic acid

To a solution of ethyl 3-(3-(trifluoromethoxy)phenoxy)propanoate (1.0 g,3.42 mmol) in THF (8 mL) was added a solution of lithium hydroxide(164mg, 6.83 mmol) in water (4 mL). The reaction was stirred at roomtemperature overnight. The reaction was neutralized with diluted HCl andextracted with ethyl acetate. The organic phase was washed with brine,dried over sodium sulfate, and concentrated to give3-(3-(trifluoromethoxy)phenoxy)propanoic acid (0.9 g, 99.1% yield) ascolorless oil which was used without purification.

Step 3N-(6-amino-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(3-(trifluoromethoxy)phenoxy)butanamide

To a solution of5,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (100mg, 0.362 mmol, Intermediate 59) in ethanol (3 mL) was added3-(3-(trifluoromethoxy)phenoxy)propanoic acid (96 mg, 0.364 mmol) andEDCI (105 mg, 0.546 mmol). The reaction was stirred at room temperaturefor 3 h. Then the mixture was diluted with water and the precipitate wascollected by filtration and rinsed with water. The solids were thendissolved in ethyl acetate. This organic solution was dried over sodiumsulfate and concentrated to giveN-(6-amino-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(3-(trifluoromethoxy)phenoxy)butanamide(150 mg, 79.3%) as a yellow solid. LCMS retention time 1.422 min; LCMSMH⁺ 523.

Step 41-(4-methoxybenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione

To a solution ofN-(6-amino-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(3-(trifluoromethoxy)phenoxy)butanamide(150 mg, 0.287 mmol) in ethanol (7 mL) was added 2N NaOH (1 mL). Themixture was stirred at 80° C. for 3 h. The reaction was neutralized withsaturated ammonium chloride and the product precipitated. The solidswere collected and washed with water. The solids were dissolved in ethylacetate, dried over sodium sulfate and concentrated to give1-(4-methoxybenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione(130 mg, 89.7%) as a light yellow solid. LCMS retention time 1.635 min;LCMS MH⁺ 505.

Intermediate 618-chloro-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione

Step 1 2-amino-7-(4-chlorobenzyl)-1H-purin-6(7H)-one

To a solution of2-amino-9-((2R,3S,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one(14 g, 49.47 mmol) in DMSO (50 mL) was added1-chloro-4-(chloromethyl)benzene (10 g, 62.16 mmol). The reaction wasstirred at 50° C. overnight. The mixture was cooled to room temperatureand HCl (50 mL, 10% w.w) was added. The reaction was stirred at 70° C.for 2 h. The reaction was cooled and the precipitate was collected andwashed with water and ethanol. The product was dried under vacuum togive 2-amino-7-(4-chlorobenzyl)-1H-purin-6(7H)-one (10 g, 74.1% yield)as grey solid. LCMS retention time 0.529 min; LCMS MH⁺ 276.

Step 2 7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione

To a solution of 2-amino-7-(4-chlorobenzyl)-1H-purin-6(7H)-one (6.8 g,24.7 mmol) in acetic acid (80 mL) and water (10 mL) was added a solutionof sodium nitrite (3.4 g, 24.7 mmol) in water (10 mL) dropwise at 50° C.The reaction was stirred at 50° C. for 1 h. The mixture was cooled toroom temperature and stirred for another 1.5 h. The precipitate wascollected, washed with water and ethanol, and dried in vacuo to give7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione (6.5 g, 95.3% yield) asyellow solid. LCMS retention time 0.635 min; LCMS MH⁺ 277.

Step 3 8-chloro-7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione

To a solution of 7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione (2.2 g,7.97 mmol) in THF (30 mL) was added NCS (1.1 g, 8.27 mmol) at 0° C. inportions. Then the resulting mixture was stirred at room temperatureuntil it became a clear solution. The reaction was immediately quenchedwith ice-water and concentrated. The residue was extracted with ethylacetate. The organic phase was washed with saturated sodium bicarbonateand brine, dried over sodium sulfate, and concentrated to give a crudeproduct. This material was purified by silica gel chromatography elutingwith DCM/methanol (50:1 to 20:1) to give8-chloro-7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione (450 mg, 18.2%yield) as white solid. LCMS retention time 1.071; LCMS MH⁺-58 311.

Step 48-chloro-7-(4-chlorobenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of 8-chloro-7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione(450 mg, 1.45 mmol) in DMF (20 mL) was added potassium carbonate (0.4 g,2.90 mmol), followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.7 mL,3.96 mmol) at 0° C. The resulting mixture was stirred at 60° C. for 16h. The mixture was partitioned between ethyl acetate and water. Thecombined organic phase was washed with brine, dried over sodium sulfate,and concentrated to give crude product. This material was purified bysilica gel chromatography eluting with petroleum/ethyl acetate (3:1 to1:1) to give8-chloro-7-(4-chlorobenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(250 mg, 39.2% yield) as yellow oil. LCMS retention time 1.886; LCMSMH⁺-28 413.

Step 57-benzyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-chloro-7-(4-chlorobenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(250 mg, 0.568 mmol) in DMF (30 mL) was added(3-bromopropoxy)(tert-butyl)dimethylsilane (0.2 g, 0.794 mmol), followedby potassium carbonate (160 mg, 1.13 mmol). The mixture was stirred at70° C. overnight. The reaction was cooled and partitioned between ethylacetate and water. The combined organic phase was washed with brine,dried over sodium sulfate, and concentrated to give7-benzyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(340 mg, 97.4% yield) as colorless oil. LCMS retention time 4.675 min;LCMS MH⁺ 613.

Step 68-chloro-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-benzyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(340 mg, 0.56 mmol) in ethyl alcohol (20 mL) was added concentrated HCl(2 mL). The mixture was stirred at 80° C. overnight. The reaction wasconcentrated, neutralized with saturated sodium bicarbonate, extractedwith ethyl acetate. The organic phase was washed with brine, dried oversodium sulfate, and concentrated to give8-chloro-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione(180 mg, 87.5% yield) as colorless oil. LCMS retention time 1.990 min;LCMS MH⁺ 369.

Intermediate 628-bromo-7-(4-fluorobenzyl)-3-methyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione

Steps 1 and 28-bromo-7-(4-fluorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the methods of intermediate 8,step 2 and intermediate 14 to give8-bromo-7-(4-fluorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(26 g, 64.3% yield) as white solid. LCMS retention time 1.694 min; LCMSMH⁺-THP 411.

Step 38-bromo-7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-fluorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(26 g, 52.5 mmol) in ethanol (500 mL) was added concentrated HCl (50 mL)and the mixture was stirred at room temperature for 1 h. The mixture wasconcentrated to half its volume and the product precipitated. The solidswere collected and washed with water and ethanol; then dried undervacuum to give8-bromo-7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(18.1 g, 83.9% yield) as white solid. LCMS retention time 1.243 min;LCMS MH⁺ 411.

Intermediate 638-bromo-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of intermediate 62 togive8-bromo-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(21 g, 93.1% yield) as white solid. LCMS retention time 1.375 min; LCMSMH⁺ 429.

Intermediate 647-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonylchloride

Step 1 7-(4-chlorobenzyl)-8-mercapto-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of intermediate 7 togive 7-(4-chlorobenzyl)-8-mercapto-3-methyl-1H-purine-2,6(3H,7H)-dione(710 mg, 81.5% yield) as yellow solid. LCMS retention time 0.973 min;LCMS MH⁺ 323.

Step 27-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonylchloride

To a solution of7-(4-chlorobenzyl)-8-mercapto-3-methyl-1H-purine-2,6(3H,7H)-dione (400mg, 1.24 mmol) in concentrated sulfuric acid (5 mL) was added aqueoussodium hypochlorite solution (5 mL, 5% active chlorine) dropwise at 0°C. and the mixture was stirred at room temperature for 15 min. Themixture was poured into ice-water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried and concentrated to give7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonylchloride (230 mg, 47.6% yield) as brown solid, which was directly usedimmediately without purification.

The following intermediates 65-71 were prepared using the method ofintermediate 5,

Intermediate 65 2-(3,5-bis(trifluoromethyl)phenoxy)ethanol

Light yellow oil, mg, 87.6% yield. TLC petroleum ether/ethyl acetate(1:2), UV detection, Rf=0.4

Intermediate 66 2-(3-chlorophenoxy)ethanol

Light yellow oil, 350 mg, 89.1% yield. TLC petroleum ether/ethyl acetate(1:2), UV detection, Rf=0.4

Intermediate 67 2-(m-tolyloxy)ethanol

Light yellow oil, 357 mg, 91% yield. TLC petroleum ether/ethyl acetate(1:2), UV detection, Rf=0.35

Intermediate 68 2-(3-(trifluoromethyl)phenoxy)ethanol

Light yellow oil, 332 mg, 81.9% yield. TLC petroleum ether/ethyl acetate(1:2), UV detection, Rf=0.4

Intermediate 69 2-(4-(trifluoromethoxy)phenoxy)ethanol

Light yellow oil, 100 mg, 78.9% yield. TLC petroleum ether/ethyl acetate(1:2), UV detection, Rf=0.4

Intermediate 70 2-(2-(trifluoromethoxy)phenoxy)ethanol

Light yellow oil, 105 mg, 85% yield. TLC petroleum ether/ethyl acetate(1:2), UV detection, Rf=0.4

Intermediate 71 2-(4-chloro-3-(trifluoromethyl)phenoxy)ethanol

Light yellow oil, 100 mg, 81% yield. TLC petroleum ether/ethyl acetate(1:2), UV detection, Rf=0.4

Intermediate 72 (2-hydroxycyclopentyl)methyl methanesulfonate

Step 1 2-(hydroxymethyl)cyclopentanol

To a solution of ethyl 2-oxocyclopentanecarboxylate (1 g, 6.41 mmol) inanhydrous THF (40 mL) was added lithium bis(trimethylsilyl)amide (6.41mL, 6.41 mmol, 1 mmol/L in THF) at 0° C. under nitrogen. The reactionwas stirred at 0° C. for 40 min. Then LAH (500 mg, 13.2 mmol) was addedin portions into the above solution at 0° C. The reaction was stirred at0° C. for 1 h. The mixture was quenched with ice-water, filtered and thefilter cake washed with ethyl acetate. The filtrate was washed withbrine, dried over sodium sulfate, and concentrated to give a crudeproduct, which was purified by silica gel chromatography eluting withDCM/methanol (30:1 to 10:1) to give 2-(hydroxymethyl)cyclopentanol (40mg, 5.4%) as yellow oil. ¹H-NMR (CDCl₃) δ 4.03-4.05 (m, 1H), 3.76-3.80(q, 1H), 3.54-3.59 (t, 1H), 1.57-2.01 (m, 7H).

Step 2 (2-hydroxycyclopentyl)methyl methanesulfonate

The title compound was prepared using the method of intermediate 42 togive (2-hydroxycyclopentyl)methyl methanesulfonate (50 mg, 73.5% yield)as yellow oil.

Intermediate 731-(3-(benzyloxy)cyclobutyl)-8-chloro-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 1 ethyl4-(3-(3-(benzyloxy)cyclobutyl)ureido)-1-(4-chlorobenzyl)-1H-imidazole-5-carboxylate

To a solution of 3-(benzyloxy)cyclobutanecarboxylic acid (442 mg, 2.14mmol) in toluene (10 mL) was added diphenylphosphoryl azide (589 mg,2.14 mmol) followed by TEA (216 mg, 2.14 mmol). The reaction was stirredat room temperature for 30 min. Ethyl4-amino-1-(4-chlorobenzyl)-1H-imidazole-5-carboxylate (300 mg, 1.07mmol) was added to the mixture and the resulting mixture was stirred at110° C. for 6 h. The reaction was partitioned between ethyl acetate andbrine. The organic phase was dried and concentrated to give a crudeproduct, which was purified by silica gel chromatography eluting withDCM/methanol (50:1) to give ethyl4-(3-(3-(benzyloxy)cyclobutyl)ureido)-1-(4-chlorobenzyl)-1H-imidazole-5-carboxylate(310 mg, 59.9 yield) as yellow solid. LCMS retention time 1.909 min;LCMS MH⁺ 483.

Step 21-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione

To a solution of ethyl4-(3-(3-(benzyloxy)cyclobutyl)ureido)-1-(4-chlorobenzyl)-1H-imidazole-5-carboxylate(310 mg, 0.64 mmol) in ethanol (50 mL) was added freshly prepared sodiumethoxide (87.4 mg, 1.28 mmol) and the reaction was heated at reflux for4 h. The reaction was cooled and concentrated. The residue waspartitioned between ethyl acetate and brine. The organic layer was driedand concentrated to give1-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione(240 mg, 85.5% yield) as a yellow solid. LCMS retention time 1.764 min;LCMS MH⁺ 437.

Step 31-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione

To a solution of1-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(240 mg, 0.62 mmol) in DMF (5 mL) was added iodomethane (105.3 mg, 0.74mmol) followed by potassium carbonate (128 mg, 0.93 mmol) and thereaction was stirred at room temperature for 16 h. The reaction waspartitioned between ethyl acetate and brine. The organic phase was driedand concentrated to give1-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(220 mg, 78.9% yield) as a yellow solid. LCMS retention time 1.914 min;LCMS MH⁺ 451.

Step 41-(3-(benzyloxy)cyclobutyl)-8-chloro-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of1-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(220 mg, 0.49 mmol) in DMF (3 mL) was added NCS (71.7 mg, 0.54 mmol) inportions at 0° C. The reaction was stirred at room temperature for 4 h.The reaction was partitioned between ethyl acetate and saturated aqueoussodium bicarbonate. The organic phase was washed with brine, dried andconcentrated to give a crude product, which was purified by silica gelchromatography eluting with DCM/methanol (60:1) to give1-(3-(benzyloxy)cyclobutyl)-8-chloro-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(170 mg, 71.8% yield) as yellow solid. LCMS retention time 2.079 min;LCMS MH⁺ 485.

Intermediate 74 3-hydroxycyclopentyl methanesulfonate

The title compound was prepared using the method of intermediate 42 step1 to give 3-hydroxycyclopentyl methanesulfonate (100 mg, 89.1% yield) asyellow oil which was used without characterization.

Intermediate 75 benzyl 3-(methylsulfonyloxy)cyclobutanecarboxylate

The title compound was prepared using the method of intermediate 42 togive benzyl 3-(methylsulfonyloxy)cyclobutanecarboxylate (0.71 g, 79.8%yield) as yellow solid which was used without characterization.

Intermediate 76 3-(chloromethyl)-5-fluoropyridine

Step 1 (5-fluoropyridin-3-yl)methanol

To a solution of 5-fluoronicotinic acid (1.0 g, 7.09 mmol) in THF (10mL) was added TEA (0.9 mL, 7.73 mmol), followed by ethyl chloroformate(0.6 mL, 7.73 mmol) at 0° C. The reaction was stirred at roomtemperature 2 h; then it was filtered. The residue was washed with asmall amount of THF. The filtrate was chilled to 0° C. and sodiumborohydride (0.67 g, 17.73 mmol) was added, followed by dropwiseaddition of water (5 mL). The reaction was stirred at room temperatureovernight. The reaction was partitioned between ethyl acetate and water.The organic layers were combined, dried over sodium sulfate, andconcentrated to give a crude product which was used purified by a silicagel chromatography to give (5-fluoropyridin-3-yl)methanol (197 mg, 21.8%yield) as a colorless oil. LCMS retention time 0.375 min; LCMS MH⁺ 128.

Step 2 3-(chloromethyl)-5-fluoropyridine

To a solution of (5-fluoropyridin-3-yl)methanol (0.19 g, 1.50 mmol) inDCM (5 mL) was added thionyl chloride (0.19 ml, 2.6 mmol) at 0° C. Thereaction was stirred at room temperature for 2 h. The reaction wasconcentrated and the residue was dried in vacuo to yield3-(chloromethyl)-5-fluoropyridine (166 mg) which was used withoutcharacterization.

Intermediate 778-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

8-Bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (33.4 g,90.4 mmol, intermediate 8), potassium carbonate (25.0 g, 180.8 mmol) andTBAI (0.225 g) were combined in DMF (460 mL). To the mixture was added(3-bromopropoxy)(tert-butyl)dimethylsilane (25.17 g, 99.4 mmol) and thereaction was heated at 100° C. for 4 h. The reaction was cooled to roomtemperature, diluted with water (1.2 L) and extracted with ethyl acetate(3×400 mL). The combined organic extracts were washed with 1N lithiumchloride (2×500 mL), dried with magnesium sulfate, filtered and thesolvent removed under reduced pressure to give a light golden oil. Theoil was purified using 2×120 g silica gel columns eluted with 10% ethylacetate/hexanes to yield8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(38.3 g, 78% yield) as an off-white solid. LCMS retention time=5.083 minand 99% purity, LCMS MH⁺ 543. ¹H NMR (CDCl₃) δ 7.29-7.34 (m, 4H), 5.50(s, 2H), 4.08 (t, 2H, J=8 Hz), 3.70 (t, 2H, J=8 Hz), 3.53 (s, 3H),1.83-1.90 (m, 2H), 0.86 (s, 9H), 0.02 (s, 6H).

Intermediate 788-chloro-7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione

Step 1 7-allyl-2-amino-1H-purin-6(7H)-one

To a solution of2-amino-9-((2R,3S,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one(50 g, 176.7 mmol) in DMSO (150 mL) was added allyl bromide (36 mL, 420mmol), the mixture was stirred at room temperature overnight undernitrogen atmosphere. The reaction was chilled to 0° C. concentrated HCl(100 mL) was added and the reaction was stirred at 70° C. for 4 h. Thereaction was cooled to room temperature, poured into water (800 mL), andneutralized with 6N sodium hydroxide to pH 7-8. The solids that formedwere collected and the filter cake was washed with water and ethanol,then dried under vacuum to give 7-allyl-2-amino-1H-purin-6(7H)-one (20g, 59.2% yield) as yellow solid. LCMS retention time 0.330 min; LCMS MH⁺192.

Step 2 7-allyl-1H-purine-2,6(3H,7H)-dione

To a solution of 7-allyl-2-amino-1H-purin-6(7H)-one (20 g, 104.7 mmol)in acetic acid (500 mL) and water (70 mL) was added a solution of sodiumnitrite (30 g, 434.8 mmol) in water (70 mL) dropwise at 50° C. Thereaction was stirred at 50° C. for 1 h. The reaction was concentratedand poured into ice-water. The solids that formed were filtered and thefilter cake was washed with water and ethanol, then dried under vacuumto give 7-allyl-1H-purine-2,6(3H,7H)-dione (15 g, 74.4% yield) as yellowsolid. LCMS retention time 0.555 min; LCMS MH⁺ 193.

Step 3 7-allyl-3-ethyl-1H-purine-2,6(3H,7H)-dione

To a solution of 7-allyl-1H-purine-2,6(3H,7H)-dione (15 g, 78.13 mmol)in DMF (200 mL) was added potassium carbonate (23.7 g, 171.74 mmol),followed by dropwise addition of iodoethane (3.6 mL, 44.54 mmol). Thereaction was stirred at room temperature overnight. The reaction wasconcentrated and partitioned between ethyl acetate and water. Theorganic phase was washed with brine and dried over sodium sulfate, andconcentrated to give a crude product which was purified by silica gelchromatography eluting with petroleum/ethyl acetate (6:1 to 3:1) to give7-allyl-3-ethyl-1H-purine-2,6(3H,7H)-dione (7 g, 40.7% yield) as yellowsolid. LCMS retention time 0.402 min; LCMS MH⁺ 221.

Step 4 7-allyl-8-chloro-3-ethyl-1H-purine-2,6(3H,7H)-dione

To a solution of 7-allyl-3-ethyl-1H-purine-2,6(3H,7H)-dione (7 g, 31.82mmol) in DMF (50 mL) was added NCS (5 g, 37.45 mmol) in portions at 0°C. The resulting mixture was stirred at room temperature for 5 h undernitrogen. The reaction was partitioned between ethyl acetate and water.The organic phase was washed with brine, dried over sodium sulfate, andconcentrated to give 7-allyl-8-chloro-3-ethyl-1H-purine-2,6(3H,7H)-dione(11.8 g, ˜50% pure) as light yellow oil. LCMS retention time 0.764 min;LCMS MH⁺ 255.

Step 57-allyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-8-chloro-3-ethyl-1H-purine-2,6(3H,7H)-dione

To a solution of 7-allyl-8-chloro-3-ethyl-1H-purine-2,6(3H,7H)-dione(6.8 g, 26.77 mmol) in DMF (50 mL) was added(3-bromopropoxy)(tert-butyl)dimethylsilane (8 g, 31.75 mmol), followedby potassium carbonate (5 g, 36.23 mmol) and TBAI (5 mg, 0.014 mmol).The reaction was stirred at 60° C. overnight. The reaction was cooled toroom temperature and partitioned between ethyl acetate and water. Theorganic phase was washed with brine, dried over sodium sulfate, andconcentrated to give a crude product which was purified by silica gelchromatography eluting with petroleum/ethyl acetate (15:1 to 1:1) togive7-allyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-8-chloro-3-ethyl-1H-purine-2,6(3H,7H)-dione(5.88 g, 51.6% yield) as a colorless oil. LCMS retention time 2.224 min;LCMS MH⁺ 427.

Step 67-allyl-8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-allyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-8-chloro-3-ethyl-1H-purine-2,6(3H,7H)-dione(3.8 g, 8.92 mmol) in ethanol (20 mL) was added concentrated HCl (2 mL).The mixture was stirred at room temperature for 0.5 h. The mixture wasconcentrated and partitioned between ethyl acetate and saturated sodiumbicarbonate. The organic phase was washed with brine and dried oversodium sulfate, and concentrated to give7-allyl-8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione(3.8 g) as yellow oil, which was used without purification. LCMSretention time 0.999 min; LCMS MH⁺ 313.

Step 7 8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-allyl-8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione(3.8 g, 12.18 mmol) in THF (40 mL) and DMSO (10 mL) was addedtetrakis(triphenylphosphine)palladium(0) (800 mg, 0.693 mmol) andmorpholine (5.4 mL, 62.07 mmol). The reaction was degassed and refilledwith nitrogen 3 times. The reaction was stirred at room temperatureovernight. The mixture was poured into water (20 mL) and ethyl acetate(100 mL). The solid precipitate was collected, washed with ethylacetate, and dried under vacuum to give8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (2.2 g,66.4% yield) as grey solid. LCMS retention time 0.404 min; LCMS MH⁺ 273.

Step 88-chloro-7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (2.2 g,8.09 mmol) in DMF (10 mL) was added 1-(bromomethyl)-4-chlorobenzene(2.47 g, 12.11 mmol), followed by potassium carbonate (2.23 g, 16.18mmol) and TBAI (15 mg, 0.042 mmol). The reaction was stirred at 50° C.for 2 h. The reaction was cooled to room temperature and partitionedbetween ethyl acetate and water. The organic phase was washed with brineand dried over sodium sulfate, and concentrated to give a crude productwhich was purified by silica gel chromatography eluting withpetroleum/ethyl acetate (5:1 to 1:2) to give8-chloro-7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione(2.3 g, 71.8% yield) as white solid. LCMS retention time 1.485 min; LCMSMH⁺ 397.

Intermediate 79 3,3,3-trifluoropropyl methanesulfonate

To a solution of 3,3,3-trifluoropropan-1-ol (500 mg, 4.38 mmol) in DCM(10 mL) was added TEA (1.22 mL, 8.77 mmol) followed by dropwise additionof methanesulfonyl chloride (0.51 mL, 6.58 mmol) at 0° C. The resultingmixture was stirred at room temperature for 2 h. The reaction wasdiluted with DCM and the organic phase washed with brine, dried andconcentrated to give crude product which was purified via silica gelchromatography eluting with petroleum ether/ethyl acetate (5:1) to give3,3,3-trifluoropropyl methanesulfonate (490 mg, 58.2% yield) as lightyellow oil. TLC (petroleum ether/ethyl acetate=3:1), Rf=0.6.

Intermediate 803-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-1H-purine-2,6(3H,7H)-dione

Step 13-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(500 mg, 1.06 mmol, intermediate 12, step 2) in DMF (6 mL) was added3,3,3-trifluoropropyl methanesulfonate (305 mg, 1.59 mmol) followed bypotassium carbonate (439 mg, 3.17 mmol). The reaction was stirred at 60°C. overnight. The mixture was diluted with ethyl acetate and extractedwith brine. The organic phase was dried and concentrated to give3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(510 mg, 84.6% yield) as yellow syrup. LCMS retention time 2.275 min;LCMS MH⁺ 569.

Step 23-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared as intermediate 17, step 2 to give3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-1H-purine-2,6(3H,7H)-dione(228 mg, 56.3% yield) as white solid. LCMS retention time 1.626 min;LCMS MH⁺ 439.

Intermediate 81 8-Bromo-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione

8-Bromo-3-methyl-1H-purine-2,6(3H,7H)-dione (2.0 g, 8.16 mmol),diisopropylethylamine (2.13 mL, 12.24 mmol) and 1-bromo-3-methylbutane(0.98 mL, 8.16 mmol) were combined in DMF (20 mL) and stirred at roomtemperature for 15 h. The reaction was diluted with water (200 mL) andextracted with ethyl acetate (3×100 mL). The combined extracts werewashed with 1 N LiCl (2×100 mL), dried with magnesium sulfate, filteredand evaporated under reduced pressure to give8-bromo-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (2.2 g, 78%yield) as a white solid. LCMS retention time=2.654 min and 98% purity,LCMS MH⁺ 315.

Intermediate 828-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione

8-Bromo-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (2.0 g, 6.35mmol), (3-bromoprpoxy)(tert-butyl)dimethylsilane (1.77 g, 6.98 mmolintermediate 81), potassium carbonate (1.76 g, 12.70 mmoL) and TBAI(0.020 g) were combined in DMF (45 mL) and stirred at room temperaturefor 6 h. The reaction was diluted with water (200 mL) and extracted withethyl acetate (3×100 mL). The combined extracts were washed with 1 NLiCl (2×100 mL), dried with magnesium sulfate, filtered and evaporatedunder reduced pressure to leave a golden oil. The oil was purified usinga 40 g silica gel flash column eluted with 10% ethyl acetate/hexanes togive8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione(2.73 g, 88% yield) as a clear oil: LCMS retention time=5.271 minutesand 92% purity, LCMS MH⁺=489.

Intermediate 837-Benzyl-8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the methods of intermediates 81and 82. Light golden oil, 15.5 g, 100% yield: LCMS retention time=4.872minutes and 96% purity, LCMS MH⁺=509.

EXAMPLES Example 17-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (240 mg,0.649 mmol, intermediate 8) in dimethyl formamide (5 mL) was added3-(trifluoromethyl)phenol (105 mg, 0.649 mmol) followed by potassiumcarbonate (107 mg, 0.779 mmol). The resulting mixture was stirred at 80°C. for 6 h. The mixture was diluted with ethyl acetate (15 mL) andextracted with brine and saturated aqueous ammonium chloride solution.Then the organic phase was dried and concentrated to give a crude solidproduct which was collected and washed with ethanol to give7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione(237 mg, 81.1% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 11.24 (s, 1H),7.77 (s, 1H), 7.69-7.71 (m, 3H), 7.43 (s, 4H), 5.42 (s, 2H), 3.22 (s,3H). LCMS retention time 2.306 min; LCMS MH⁺ 451.

Example 27-(4-chlorobenzyl)-1-ethyl-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione(50 mg, 0.11 mmol, example 1) in DMF (1 mL) was added iodoethane (18.7mg, 0.12 mmol) followed by potassium carbonate (23 mg, 0.16 mmol). Thenthe mixture was stirred at 50° C. for 3 h. The mixture was diluted withethyl acetate and extracted with brine and saturated aqueous ammoniumchloride solution. The organic phase was dried and concentrated to givecrude solid product which was collected and washed with ethanol to give7-(4-chlorobenzyl)-1-ethyl-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione(15 mg, 26.7% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.77 (s, 1H),7.69-7.73 (m, 3H), 7.43 (s, 4H), 5.46 (s, 2H), 3.91-3.93 (q, 2H), 3.29(s, 3H), 1.11-1.14 (t, 3H). LCMS retention time 3.109 min; LCMS MH⁺ 479.

Example 32-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethyl)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-methylacetamide

The title compound was prepared using the method of example 2 except acatalytic amount of TBAI was added to give2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethyl)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-methylacetamide(36 mg, 62.1% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.97-7.98 (m,1H), 7.79 (s, 1H), 7.69-7.74 (m, 3H), 7.44 (s, 4H), 5.45 (s, 2H), 4.43(s, 2H), 3.91-3.93 (q, 2H), 3.29 (s, 3H), 2.58-2.59 (d, 3H). LCMSretention time 2.547 min; LCMS MH⁺ 522.

Example 47-(4-chlorobenzyl)-3-methyl-1-((5-methylisoxazol-3-yl)methyl)-8-(3-(trifluoromethyl)phen-oxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 2 except acatalytic amount of TBAI was added to give7-(4-chlorobenzyl)-3-methyl-1-((5-methylisoxazol-3-yl)methyl)-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione(29 mg, 39.9% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.79 (s, 1H),7.69-7.73 (m, 3H), 7.44 (s, 4H), 6.12 (s, 1H), 5.45 (s, 2H), 5.07 (s,1H), 3.30 (s, 3H), 2.35 (S, 3H). LCMS retention time 2.920 min; LCMS MH⁺546.

Example 57-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione(60 mg, 0.133 mmol, example 1) in DMF (1 mL) was added 2-bromoethanol(16.5 mg, 0.133 mmol) and cesium carbonate (86.6 mg, 0.266 mmol). Theresulting mixture was subjected to microwave irradiation at 120° C. for20 min in a sealed tube. The mixture was diluted with ethyl acetate (5mL) and extracted with saturated aqueous ammonium chloride solution. Theorganic phase was dried and concentrated to give crude product which waspurified preparative HPLC to give7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione(19 mg, 28.8% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.76 (s, 1H),7.69-7.71 (m, 3H), 7.43 (s, 4H), 5.45 (s, 2H), 4.77-4.78 (d, 1H),3.95-3.98 (t, 2H), 3.51-3.54 (t, 2H), 3.28 (s, 3H). LCMS retention time2.608 min; LCMS MH⁺ 495.

Example 67-(4-chlorobenzyl)-1-(2-(dimethylamino)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dionehydrochloride

Step 11-(2-bromoethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.215 mmol, Intermediate 9) in DMF (3 mL) was added1,2-dibromoethane (100 mg, 0.532 mmol), followed by potassium carbonate(60 mg, 0.429 mmol). The mixture was stirred at 80° C. overnight. Themixture was diluted with ethyl acetate and water, and the phases wereseparated. The organic phase was washed with brine, dried over sodiumsulfate, filtered and concentrated to give crude product, which waspurified by recrystallization from ethanol to give1-(2-bromoethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(120 mg, 97.6% yield) as white solid. LCMS retention time 2.103 min;LCMS MH⁺ 573.

Step 27-(4-chlorobenzyl)-1-(2-(dimethylamino)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dionehydrochloride

1-(2-bromoethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(120 mg, 0.0.210 mmol) was dissolved in aqueous dimethylamine (3 mL),then the mixture was heated to 100° C. in a sealed tube with stirringovernight. The mixture was diluted with ethyl acetate and water, and thephases were separated. The organic phase was washed with brine, driedover sodium sulfate, filtered and concentrated to give crude product,which was purified by preparative HPLC and lyophilized to give7-(4-chlorobenzyl)-1-(2-(dimethylamino)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dionehydrochloride (29 mg, 25.6% yield) as white solid. ¹H-NMR (DMSO-d₆) δ9.67 (s, 1H), 7.64-7.60 (t, 1H), 7.47-7.41 (m, 6H), 7.36-7.34 (m, 1H),5.46 (s, 2H), 4.23-4.21 (m, 2H), 3.37-3.34 (m, 2H), 3.31 (s, 3H),2.87-2.86 (d, 6H). LCMS retention time 2.174 min; LCMS MH⁺ 538.

The following examples 7a through 7k were prepared using the method ofexample 6, step 1.

Example 7a7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 6, step 1and purified via preparative HPLC to give7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(10 mg, 17.3% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.57-7.53 (t, 1H),7.46-7.44 (d, 2H), 7.37-7.33 (m, 4H), 7.26-7.24 (d, 1H), 5.49 (s, 2H),4.13-4.09 (t, 1H), 3.64-3.60 (t, 2H), 3.42 (s, 3H), 1.89-1.86 (m, 2H).LCMS retention time 3.059 min; LCMS MH⁺ 525.

Example 7b2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)-N,N-dimethylacetamide

The title compound was prepared with 2-chloro-N,N-dimethylacetamide andpurified via preparative HPLC to give2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)-N,N-dimethylacetamide(20 mg, 17.2% yield) as white solid. ¹H-NMR (400 Hz, DMSO-d₆)δ=7.64-7.59 (t, 1H), 7.55 (s, 1H), 7.48-7.40 (m, 5H), 7.35-7.33 (d, 1H),5.42 (s, 2H), 4.69 (s, 2H), 3.30 (s, 3H), 3.07 (s, 3H), 2.84 (s, 3H).LCMS retention time 3.079 min; LCMS MH⁺ 552.

Example 7c7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared with 1,1,1-trifluoro-3-iodopropane togive7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-1H-purine-2,6(3H,7H)-dione(30 mg, 35.6% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.64-7.59 (t,1H), 7.50 (s, 1H), 7.45-7.41 (m, 5H), 7.35-7.33 (d, 1H), 5.44 (s, 2H),4.15-4.12 (t, 2H), 3.22 (s, 3H), 2.63-2.55 (m, 2H). LCMS retention time3.575 min; LCMS MH⁺ 563.

Example 7d7-(4-chlorobenzyl)-1-(4-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 58, step 1except the reaction was facilitated by microwave irradiation at 120° C.for 45 min to give7-(4-chlorobenzyl)-1-(4-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(10 mg, 8.9% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.63-7.58 (t,1H), 7.49 (s, 1H), 7.44-7.42 (m, 5H), 7.38-7.32 (d, 1H), 5.44 (s, 2H),4.41 (s, 1H), 3.89-3.86 (t, 2H), 3.39-3.34 (m, 2H), 3.29 (s, 3H),1.61-1.54 (m, 2H), 1.45-1.38 (m, 2H). LCMS retention time 3.053 min;LCMS MH⁺ 539.

Example 7e7-(4-chlorobenzyl)-1-(5-hydroxypentyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared with 5-bromopentan-1-ol to give7-(4-chlorobenzyl)-1-(5-hydroxypentyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(30 mg, 20.9% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.63-7.58 (t,1H), 7.49 (s, 1H), 7.44-7.42 (m, 5H), 7.34-7.32 (d, 1H), 5.44 (s, 2H),4.40-3.78 (t, 1H), 3.88-3.84 (t, 2H), 3.40-3.36 (m, H), 3.29 (s, 3H),1.56-1.52 (m, 2H), 1.46-1.42 (m, 2H), 1.31-1.27 (m, 2H). LCMS retentiontime 3.057 min; LCMS MH⁺ 553.

Example 7f7-(4-chlorobenzyl)-1-(2-hydroxy-3-methoxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared with 1-chloro-3-methoxypropan-2-ol andwith heating to 130° C. White solid, 70 mg, 58.8% yield: ¹H-NMR (400 Hz,CD₃OD) δ 7.57-7.53 (t, 1H), 7.47-7.44 (d, 2H), 7.37-7.33 (m, 4H),7.26-7.24 (d, 1H), 5.49 (s, 2H), 4.24-4.19 (m, 1H), 4.12-4.11 (m, 1H),4.04-3.99 (m, 1H), 3.45-3.42 (m, 5H), 3.36-3.30 (d, 3H). LCMS retentiontime 3.044 min; LCMS MH⁺ 555.

Example 7g7-(4-chlorobenzyl)-1-(2-methoxyethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared with 1-bromo-2-methoxyethane andpurified via preparative HPLC. White solid, 40 mg, 50.9% yield: ¹H-NMR(DMSO-d₆) δ 7.63-7.59 (t, 1H), 7.50 (s, 1H), 7.45-7.43 (m, 5H),7.34-7.32 (d, 1H), 5.44 (s, 2H), 4.08-4.05 (t, 2H), 3.88-3.84 (t, 2H),3.52-3.49 (t, 2H), 3.29 (s, 3H), 3.24 (s, 3H). LCMS retention time 3.322min; LCMS MH⁺ 525.

Example 7h7-(4-chlorobenzyl)-1-(isoxazol-5-ylmethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared with 5-(chloromethyl)isoxazole and thereaction was catalyzed with TBAI. The crude product was purified bypreparative HPLC to give7-(4-chlorobenzyl)-1-(isoxazol-5-ylmethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(21mg, 8.9% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 8.50-8.49 (d, 1H),7.64-7.59 (t, 1H), 7.51 (s, 1H), 7.46-7.43 (m, 5H), 7.36-7.33 (d, 1H),6.39-6.38 (d, 1H), 5.44 (s, 2H), 5.22 (s, 2H), 3.32 (s, 3H). LCMSretention time 3.269 min; LCMS MH⁺ 548.

Example 7iN-tert-butyl-1-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)methanesulfonamide

The title compound was prepared withN-tert-butyl-1-chloromethanesulfonamide. White solid, 180 mg, 68.3%yield: ¹H-NMR (DMSO-d₆) δ 7.64-7.59 (t, 1H), 7.49 (s, 1H), 7.45-7.39 (m,6H), 7.35-7.33 (d, 1H), 7.14 (s, 1H), 5.45 (s, 2H), 5.21 (s, 2H), 3.31(s, 3H), 1.28 (s, 9H). LCMS retention time 3.426 min; LCMS MH⁺ 616.

Example 7j7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compounds prepared with 2-bromoethanol. White solid, 11 mg,16.7% yield: ¹H-NMR (DMSO-d₆) δ 7.58-7.62 (m, 1H), 7.49 (s, 1H),7.41-7.43 (m, 5H), 7.31-7.32 (d, 1H), 5.44 (s, 2H), 4.76-4.79 (t, 1H),3.95-3.98 (t, 2H), 3.50-3.54 (t, 2H), 3.28 (s, 3H). LCMS retention time2.690 min; LCMS MH⁺ 511.

Example 7k7-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared with3-hydroxybutyl-4-methylbenzenesulfonate (intermediate 33). White solid,70 mg, 61.9% yield: ¹H-NMR (DMSO-d₆) δ 7.59-7.55 (t, 1H), 7.46-7.39 (d,6H), 7.30-7.28 (d, 1H), 5.41 (s, 2H), 4.49-4.48 (d, 1H), 4.02-3.97 (m,1H), 3.84-3.79 (m, 1H), 3.64-3.61 (m, 1H), 3.26 (s, 3H), 1.59-1.52 (m,2H), 1.06-1.05 (d, 3H). LCMS retention time 3.159 min; LCMS MH⁺ 539.

Example 83-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanenitrile

To a solution of7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.215 mmol, Intermediate 9) in a mixed solution of THF (3 mL)and acetonitrile (5 mL) was added TBAH (0.05 ml, 0.193 mmol) andacrylonitrile (40 mg, 0.642 mmol). The mixture was stirred at 60° C.overnight. Then the mixture was diluted with DCM and water, and thephases were separated. The organic phase was washed with brine, driedover sodium sulfate, filtered and concentrated to give crude product.This crude material was purified by silica gel chromatography elutingwith petroleum/ethyl acetate (3:1 to 1:1) to give3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanenitrile(75 mg, 68.8%) as white solid. ¹H-NMR (DMSO-d₆) δ 7.63-7.59 (t, 1H),7.50 (s, 1H), 7.45-7.40 (m, 5H), 7.35-7.33 (d, 1H), 5.45 (s, 2H),4.16-4.13 (t, 2H), 3.31 (s, 3H), 2.89-2.86 (t, 2H). LCMS retention time3.248 min; LCMS MH⁺ 520.

Example 92-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)aceticacid

Step 1 tert-butyl2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate

The title compound was prepared using the method of example 6, step 1 togive 200 mg (100% yield) as yellow oil which was used withoutpurification. LCMS M-^(t)Bu+H 525.

Step 22-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)aceticacid

To a solution of tert-butyl2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate(200 mg, 0.342 mmol) in DCM (5 ml) was added trifluoroacetic acid(2 ml,26.9 mmol) at 0° C. The mixture was stirred at 0° C. to room temperaturefor 3 h. Then the mixture was concentrated, diluted with DCM and water.The phases were separated and the organic phase was washed with brine,dried over sodium sulfate, filtered and concentrated to give2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)aceticacid (180 mg, 99.9% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 13.06 (s,1H), 7.64-7.59 (t, 1H), 7.55 (s, 1H), 7.48-7.43 (m, 5H), 7.36-7.34 (d,1H), 5.43 (s, 2H), 4.53 (s, 2H), 3.37 (s, 3H). LCMS retention time 2.994min; LCMS MH⁺ 525.

Example 107-(4-chlorobenzyl)-3-methyl-1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)aceticacid (80 mg, 0.152 mmol, example 9) in NMP (2 mL) was added TEA (0.1 mL,0.614 mmol), 1-methylpiperazine (0.07 mL, 0.614 mmol) andO-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (87 mg, 0.231 mmol); then the mixture was stirred at60° C. for 16 h. Then the mixture was diluted with ethyl acetate andwater, the phases were separated. The organic phase was washed withbrine, dried over sodium sulfate, filtered and concentrated to givecrude product. This crude material was purified by recrystallizationfrom methanol to give7-(4-chlorobenzyl)-3-methyl-1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(25 mg, 27.5% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.62-7.59 (t,1H), 7.55 (s, 1H), 7.49-7.39 (m, 5H), 7.36-7.34 (d, 1H), 5.43 (s, 2H),4.71 (s, 2H), 3.55-3.48 (m, 4H), 3.30 (s, 3H), 2.46-2.36 (m, 4H), 2.21(s, 3H). LCMS retention time 2.298 min; LCMS MH⁺ 607.

Example 117-(4-chlorobenzyl)-1-(3-(dimethylamino)-2-oxopropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dionehydrochloride

The title compound was prepared using the 2 step method of example 6 togive7-(4-chlorobenzyl)-1-(3-(dimethylamino)-2-oxopropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dionehydrochloride (20 mg, 25.6% yield) as white solid. ¹H-NMR (DMSO-d₆) δ10.05 (s, 1H), 7.65-7.61 (t, 1H), 7.54 (s, 1H), 7.48-7.40 (m, 5H),7.37-7.35 (d, 1H), 5.43 (s, 2H), 4.85 (s, 2H), 4.52 (s, 2H), 3.32 (s,3H), 2.80 (s, 6H). LCMS retention time 2.352 min; LCMS MH⁺ 566.

Example 127-(4-chlorobenzyl)-3-methyl-1-(2-(4-methylpiperazin-1-yl)ethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the 2 step method of example 6with 1-methylpiperazine to give7-(4-chlorobenzyl)-3-methyl-1-(2-(4-methylpiperazin-1-yl)ethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(40 mg, 38.7% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.59-7.55 (t, 1H),7.46-7.34 (m, 6H), 7.27-7.25 (d, 2H), 5.51 (s, 2H), 4.19-4.16 (t, 2H),3.43 (s, 3H), 3.33-3.32 (m, 4H), 3.03-3.93 (bs, 4H), 2.82-2.73 (t, 2H),2.69 (s, 3H). LCMS retention time 2.310 min; LCMS MH⁺ 593.

Example 137-(4-chlorobenzyl)-1-(2,3-dihydroxypropyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-3-methyl-1-(oxiran-2-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 6, step 1 togive7-(4-chlorobenzyl)-3-methyl-1-(oxiran-2-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(220 mg, 100% yield) as yellow solid which was used withoutpurification. LCMS MH⁺ 523.

Step 27-(4-chlorobenzyl)-1-(2,3-dihydroxypropyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-1-(oxiran-2-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(140 mg, 0.268 mmol) in 1,4-dioxane (10 mL) was added TFA (0.11 mL, 1.48mmol) and water (2 mL); then the mixture was stirred at 80° C. for 2 h.The mixture was concentrated; then purified by silica gel chromatographyeluting with DCM/methanol (50:1 to 20:1) to give7-(4-chlorobenzyl)-1-(2,3-dihydroxypropyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione(70 mg, 48.4% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.63-7.58 (t,1H), 7.48 (s, 1H), 7.44-7.41 (m, 5H), 7.34-7.31 (d, 1H), 5.44 (s, 2H),4.68-4.67 (d, 1H), 4.55-4.52 (m, 1H), 4.01-3.98 (m, 1H), 3.84-3.80 (m,2H), 3.33 (s, 2H), 3.29 (s, 3H). LCMS retention time 2.811 min; LCMS MH⁺541.

Example 147-(4-chlorobenzyl)-1-(3-hydroxy-2-methoxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 11-(3-(tert-butyldimethylsilyloxy)-2-hydroxypropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-1-(2,3-dihydroxypropyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.185 mmol, product of example 13) in DCM (10 mL) was addedimidazole (11 mg, 0.16 mmol) and DMAP (10 mg, 0.08 mmol) at 0° C., thentert-butylchlorodimethylsilane (40 mg, 0.27 mmol) was added in oneportion. The mixture was stirred at room temperature overnight. Themixture was diluted with DCM and water, and the phases were separated.The organic phase was washed with brine, dried over sodium sulfate,filtered and concentrated to give crude1-(3-(tert-butyldimethylsilyloxy)-2-hydroxypropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(180 mg, 100% yield) as white solid. LCMS MH⁺ 655.

Step 21-(3-(tert-butyldimethylsilyloxy)-2-methoxypropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a slurry of sodium hydride (240 mg, 9.6 mmol) in anhydrous THF (10ml) was added dropwise a solution of1-(3-(tert-butyldimethylsilyloxy)-2-hydroxypropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(124 mg, 0.19 mmol) in THF (3 mL) at 0° C. under nitrogen. The reactionwas stirred at 0° C. for 10 minutes. Then iodomethane (1.2 ml, 19.4mmol) was added dropwise and the resulting mixture was allowed to warmfrom 0° C. to room temperature over 2 h. The mixture was quenched withice-water (5 mL). The mixture was concentrated, diluted with ethylacetate and water, and the organic layer was separated. The organiclayer was dried over sodium sulfate, filtered and concentrated to givecrude product (150 mg, 100% yield) as yellow oil. LCMS MH⁺ 669.

Step 37-(4-chlorobenzyl)-1-(3-hydroxy-2-methoxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of1-(3-(tert-butyldimethylsilyloxy)-2-methoxypropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(150 mg, 0.22 mmol) in ethyl alcohol (5 mL) was added concentrated HCl(0.1 mL). The reaction was stirred for 10 minutes. Then it wasconcentrated and purified by preparative HPLC to give7-(4-chlorobenzyl)-1-(3-hydroxy-2-methoxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(18 mg, 16.2% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.63-7.59 (t,1H), 7.50 (s, 1H), 7.45-7.43 (m, 5H), 7.34-7.32 (d, 1H), 5.44 (s, 2H),4.65-4.62 (t, 1H), 4.12-4.08 (q, 1H), 3.84-3.79 (q, 1H), 3.53-3.41 (m,2H), 3.29-3.28 (d, 6H). LCMS retention time 3.089 min; LCMS MH⁺ 555.

Example 157-(4-chlorobenzyl)-1-(3-(dimethylamino)-2-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-1-(oxiran-2-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.192 mmol, example 13, step 1) in THF (10 mL) was addeddimethylamine hydrochloride (160 mg, 1.98 mmol) and lithium perchlorate(20 mg, 0.189 mmol). The mixture was stirred at 25° C. in a sealed tubefor 2 h. The mixture was diluted with ethyl acetate and water. Thephases were separated and the organic phase was washed with brine, driedover sodium sulfate, filtered and concentrated to give crude product.This crude material was purified via preparative HPLC to give7-(4-chlorobenzyl)-1-(3-(dimethylamino)-2-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(50 mg, 46.2% yield) as white solid. ¹H-NMR (CD₃OD) δ 8.48 (s, 1H),7.59-7.54 (t, 1H), 7.47-7.45 (d, 2H), 7.38-7.34 (m, 4H), 7.27-7.25 (d,1H), 5.51 (s, 2H), 4.34-4.31 (m, 1H), 4.23-4.18 (m, 1H), 4.07-4.02 (m,1H), 3.44 (s, 1H), 3.22-3.21 (d, 2H), 2.90 (s, 6H). LCMS retention time2.227 min; LCMS MH⁺ 568.

Example 167-(4-chlorobenzyl)-1-(3-methoxy-2-oxopropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-1-(2-hydroxy-3-methoxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(40 mg, 0.072 mmol, example 70 in methyl sulfoxide (4 mL) was addedacetic anhydride(37 mg, 0.363 mmol) dropwise. Then the mixture wasstirred at 25° C. for 16 h. The mixture was partitioned between ethylacetate and water and the organic phase was washed with brine, driedover sodium sulfate, filtered and was concentrated to give crudeproduct. This crude material was further purified preparative HPLC togive7-(4-chlorobenzyl)-1-(3-methoxy-2-oxopropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(12 mg, 30.2%) as white solid. ¹H-NMR (CD₃OD) δ 7.56-7.52 (t, 1H),7.42-7.39 (d, 2H), 7.36-7.31 (m, 4H), 7.24-7.22 (d, 1H), 5.45 (s, 2H),4.92 (s, 2H), 4.24 (s, 2H), 3.46 (s, 3H), 3.39 (s, 3H). LCMS retentiontime 3.210 min; LCMS MH⁺ 553.

Example 17N-(2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)propane-2-sulfonamide

Step 17-(4-chlorobenzyl)-1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 6, step 1with 2-(2-bromoethyl)isoindoline-1,3-dione to give7-(4-chlorobenzyl)-1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(150 mg, 72.9% yield) as a white solid. LCMS retention time 2.045 min;LCMS MH⁺ 640.

Step 21-(2-aminoethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.157 mmol) in ethanol (10 mL) was added hydrazine hydrate(2ml) dropwise, then the mixture was stirred at 80° C. for 2 h. Themixture was concentrated to give1-(2-aminoethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(100 mg, 100%) as yellow oil. LCMS MH⁺ 510.

Step 3N-(2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)propane-2-sulfonamide

To a solution of1-(2-aminoethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.197 mmol) and TEA (40 mg, 0.393 mmol) in DCM (10 mL) wasadded propane-2-sulfonyl chloride (42 mg, 0.295 mmol) dropwise at 0° C.The resulting mixture was stirred at 40° C. for 16 h. The mixture wasdiluted with DCM and water, and the phases were separated. The organicphase was washed with brine, dried over sodium sulfate, filtered andconcentrated to give crude product. This crude material wasrecrystallized from ethanol to giveN-(2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)propane-2-sulfonamide(20 mg, 16.5% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.63-7.59 (t,1H), 7.48 (s, 1H), 7.45-7.41 (m, 5H), 7.35-7.33 (d, 1H), 7.26-7.18 (m,1H), 5.45 (s, 2H), 4.01-3.97 (t, 1H), 3.29 (s, 6H). LCMS retention time3.195 min; LCMS MH⁺ 616.

Example 18(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)methanesulfonamide

A solution ofN-tert-butyl-1-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)methanesulfonamide(120 mg, 0.195 mmol, example 7i) in TFA (2 ml, 26.9 mmol) was stirred at50° C. for 16 h. The mixture was concentrated and then purified bysilica gel chromatography eluting with DCM/methanol (40:1) to give(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)methanesulfonamide(79 mg, 72.4% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.65-7.61 (t,1H), 7.49 (s, 1H), 7.47-7.41 (m, 6H), 7.36-7.35 (d, 1H), 7.05 (s, 2H),5.45 (s, 2H), 5.23 (s, 2H), 3.31 (s, 3H). LCMS retention time 3.004 min;LCMS MH⁺ 560.

Example 191-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-methylmethanesulfonamide

To a solution of7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)methanesulfonamide(0.1 g, 0.18 mmol, example 18) in DMF (3 mL) was added iodomethane (16mg, 0.18 mmol) and potassium carbonate(36 mg, 0.26 mmol). The reactionwas stirred at room temperature overnight. The mixture was partitionedbetween ethyl acetate and water. The organic layers were combined, driedover sodium sulfate, filtered and concentrated. The crude product waspurified by preparative-HPLC to give1-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8(3-(trifluoromethoxy)-phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-methylmethanesulfonamide(23 mg, 22.3% yield) as a white solid. ¹H-NMR (DMSO-d₆) δ 7.63 (t, 1H),7.50 (d, 1H), 7.41-7.46 (m, 4H), 7.34-7.37 (m, 1H), 7.19-7.23 (m, 1H),5.45 (s, 2H), 5.20 (s, 2H), 3.31 (s, 3H), 2.60 (d, 3H). LCMS retentiontime 3.097 min; LCMS MH⁺ 574

Example 208-(3,5-bis(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-3-ethyl-1-methyl-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-1-(2-(2-ethyl-1,3-dioxolan-2-yl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 6, step 1with intermediate 32 to give7-(4-chlorobenzyl)-1-(2-(2-ethyl-1,3-dioxolan-2-yl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(360 mg, 100% yield) as white solid. LCMS MH⁺ 595.

Step 27-(4-chlorobenzyl)-3-methyl-1-(3-oxopentyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 14, step 3to give7-(4-chlorobenzyl)-3-methyl-1-(3-oxopentyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(60 mg, 64.2% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.59-7.55 (t,1H), 7.46-7.39 (d, 6H), 7.31-7.29 (d, 1H), 5.39 (s, 2H), 4.06-4.03 (m,2H), 3.26 (s, 3H), 2.69-2.65 (t, 2H), 2.48-2.42 (t, 2H), 0.91-0.87 (t,3H). LCMS retention time 3.384 min; LCMS MH⁺ 551.

Example 217-(4-chlorobenzyl)-1-(3-hydroxypentyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-1-(3-oxopentyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(150 mg, 0.273 mmol, example 20) in methanol (20 mL) was added sodiumborohydride (40 mg, 1.05 mmol) at 0° C. under nitrogen. The mixture wasstirred at 0° C. for 2 h. The mixture was diluted with ethyl acetate andwater, and the phases were separated. The organic phase was washed withbrine, dried over sodium sulfate, filtered and concentrated. The crudeproduct was purified by preparative HPLC to give7-(4-chlorobenzyl)-1-(3-hydroxypentyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(50 mg, 33.5% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.63-7.58 (t,1H), 7.49 (s, 1H), 7.44-7.42 (m, 5H), 7.34-7.31 (d, 1H), 5.44 (s, 2H),4.48-4.46 (d, 1H), 4.08-4.01 (m, 1H), 3.89-3.83 (m, 1H), 3.42-3.37 (m,1H), 3.29 (s, 3H), 1.63-1.55 (m, 2H), 1.44-1.31 (m, 2H), 0.87-0.84 (t,3H). LCMS retention time 3.372 min; LCMS MH⁺ 553.

Example 227-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione

Step 18-(4-chloro-3-(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 8 using the method ofintermediate 12, step 2 to give8-(4-chloro-3-(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(77mg, 39.5% yield) as white solid. LCMS retention time 1.809 min; LCMS MH⁺485

Step 27-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 6, step 1 togive7-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione(20 mg, 24.4% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.94-7.93 (d,1H), 7.86-7.84 (d, 1H), 7.79-7.77 (m, 1H), 7.46 (s, 4H), 5.44 (s, 2H),3.94-3.89 (m, 2H), 3.29 (s, 3H), 1.14-1.10 (t, 3H). LCMS retention time3.400 min; LCMS MH⁺ 513

Example 233-benzyl-7-(4-chlorobenzyl)-1-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 13-benzyl-8-chloro-7-(4-chlorobenzyl)-1-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of8-chloro-7-(4-chlorobenzyl)-1-methyl-1H-purine-2,6(3H,7H)-dione (50 mg,0.154 mmol, intermediate 10) in DMF (3 mL) was added(bromomethyl)benzene (50 mg, 0.29 mmol) followed by potassium carbonate(40 mg, 0.29 mmol). The mixture was stirred at 40° C. overnight. Themixture was diluted with ethyl acetate and water, and the phases wereseparated. The organic phase was washed with brine, dried over sodiumsulfate, filtered and concentrated. The crude product was purified bysilica gel chromatography eluting with petroleum/ethyl acetate (5:1 to3:1) to give3-benzyl-8-chloro-7-(4-chlorobenzyl)-1-methyl-1H-purine-2,6(3H,7H)-dione(60 mg, 93.6% yield) as white solid. LCMS retention time 1.893 min; LCMSMH⁺ 415.

Step 23-benzyl-7-(4-chlorobenzyl)-1-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of3-benzyl-8-chloro-7-(4-chlorobenzyl)-1-methyl-1H-purine-2,6(3H,7H)-dione(60 mg, 0.145 mmol) in DMF (3 mL) was added 3-(trifluoromethyl)phenol(35 mg, 0.215 mmol) followed by potassium carbonate (40 mg, 0.29 mmol).The mixture was stirred at 100° C. for 2 h. The mixture was diluted withethyl acetate and water, and the phases were separated. The organicphase was washed with brine, dried over sodium sulfate, filtered andconcentrated. The give crude product was purified by preparative HPLC togive3-benzyl-7-(4-chlorobenzyl)-1-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione(31 mg, 41.7% yield) as white solid. ¹H-NMR (CDCl₃) δ 7.65 (s, 1H),7.58-7.57 (m, 2H), 7.45-7.41 (m, 5H), 7.33-7.27 (m, 5H), 5.42 (s, 2H),5.09 (s, 2H), 3.41 (s, 3H). LCMS retention time 3.649 min; LCMS (M+H)541.

The following examples 24a through 24m were prepared using the 2 stepmethod of example 23.

Example 24a7-(4-chlorobenzyl)-3-(2-hydroxyethyl)-1-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 7 mg, 10.1% yield: ¹H-NMR (CDCl₃) δ 7.57-7.51 (m, 3H),7.44-7.42 (m, 3H), 7.34-7.32 (m, 2H), 5.44 (s, 2H), 4.21-4.18 (m, 2H),3.88-3.84 (m, 2H), 3.42 (s, 3H). LCMS retention time 3.045 min; LCMS MH⁺495.

Example 24b7-(4-chlorobenzyl)-1-methyl-3-(pyridin-2-ylmethyl)-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 30 mg, 50.4% yield: ¹H-NMR (DMSO-d₆) δ 8.43-8.41 (d, 1H),7.71-7.63 (m, 5H), 7.49-7.44 (m, 4H), 7.28-7.23 (m, 2H), 5.46 (s, 2H),5.14 (s, 2H), 3.26 (s, 3H). LCMS retention time 3.279 min; LCMS MH⁺ 542.

Example 24c3-benzyl-7-(4-chlorobenzyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 15 mg, 10.8% yield: ¹H-NMR (DMSO-d₆) δ 7.61-7.56 (m, 1H),7.49 (bs, 1H), 7.41-7.39 (m, 5H), 7.31-7.24 (m, 6H), 5.41 (s, 2H), 4.99(s, 2H), 3.22 (s, 3H). LCMS retention time 3.705 min; LCMS MH⁺ 557.

Example 24d7-(4-chlorobenzyl)-3-(2-hydroxyethyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 58 mg, 18.9% yield: ¹H-NMR (DMSO-d₆) δ 7.63-7.59 (m, 1H),7.49-7.42 (m, 6H), 7.34-7.31 (m, 1H), 5.44 (s, 2H), 4.81-4.78 (t, 1H),3.94-3.90 (m, 2H), 3.60-3.37 (m, 2H), 3.24 (s, 3H). LCMS retention time3.002 min; LCMS MH⁺ 511.

Example 24e7-(4-chlorobenzyl)-1-methyl-3-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 38 mg, 62.0% yield: ¹H-NMR (DMSO-d₆) δ 8.43-8.42 (d, 1H),7.73-7.69 (m, 1H), 7.56-7.52 (t, 1H), 7.48-7.43 (m, 4H), 7.38-7.34 (m,2H), 7.29-7.23 (m, 3H), 5.45 (s, 2H), 5.15 (s, 2H), 3.26 (s, 3H). LCMSretention time 3.266 min; LCMS MH⁺ 558.

Example 24f8-(3,5-bis(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-3-ethyl-1-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 10 mg, 26.2% yield: ¹H-NMR (DMSO-d₆) δ 8.23 (s, 2H), 8.05(s, 1H), 7.48-7.39 (dd, 4H), 5.42 (s, 2H), 3.86-3.84 (m, 2H), 3.22 (s,3H), 1.14-1.11 (t, 3H). LCMS retention time 3.591 min; LCMS MH⁺ 547.

Example 24g7-(4-chlorobenzyl)-3-ethyl-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 20 mg, 20.4% yield: ¹H-NMR (DMSO-d₆) δ 7.61-7.59 (t, 1H),7.52 (s, 1H), 7.43 (s, 5H), 7.33-7.32 (d, 1H), 5.44 (s, 2H), 3.89-3.88(m, 2H), 3.24 (s, 3H), 1.17-1.13 (t, 3H). LCMS retention time 3.561 min;LCMS MH⁺ 495.

Example 24h7-(4-chlorobenzyl)-3-ethyl-1-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 20 mg, 24.5% yield: ¹H-NMR (DMSO-d₆) δ 7.79 (s, 1H),7.73-7.67 (m, 3H), 7.47-7.42 (m, 4H), 5.45 (s, 2H), 3.90-3.85 (q, 2H),3.30 (s, 3H), 1.24-1.13 (t, 3H). LCMS retention time 3.511 min; LCMS MH⁺479.

Example 24i7-(4-chlorobenzyl)-1-methyl-3-(pyridin-4-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 10 mg, 6.21% yield: ¹H-NMR (DMSO-d₆) δ 8.48-8.46 (d, 2H),7.59-7.55 (t, 1H), 7.47-7.45 (m, 5H), 7.43-7.39 (d, 1H), 7.38-7.37 (d,1H), 7.31-7.24 (m, 2H), 5.45 (s, 2H), 5.05 (s, 2H), 3.25 (s, 3H). LCMSretention time 2.856 min; LCMS MH⁺ 558.

Example 24j7-(4-chlorobenzyl)-1-methyl-3-(2-oxopropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 11 mg, 9.93% yield: ¹H-NMR (DMSO-d₆) δ 7.61-7.59 (t, 1H),7.44-7.38 (m, 6H), 7.32-7.30 (d, 1H), 5.44 (s, 2H), 4.74 (s, 2H), 3.24(s, 3H), 2.16 (s, 3H). LCMS retention time 3.210 min; LCMS MH⁺ 523.

Example 24k7-(4-chlorobenzyl)-3-(2-(2-hydroxyethoxy)ethyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 31 mg, 45.3% yield: ¹H-NMR (DMSO-d₆) δ 7.59-7.56 (t, 1H),7.44-7.37 (m, 6H), 7.31-7.29 (d, 1H), 5.42 (s, 2H), 4.01-3.98 (t, 2H),3.35 (s, 4H), 3.22 (s, 3H). LCMS retention time 2.969 min; LCMS MH⁺ 555.

Example 2417-(4-chlorobenzyl)-1-methyl-3-propyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 15 mg, 26.8% yield: ¹H-NMR (CDCl₃) δ 7.49-7.43 (m, 3H),7.35-7.31 (m, 3H), 7.24-7.15 (m, 2H), 5.44 (s, 2H), 3.97-3.93 (t, 2H),3.43 (s, 3H), 1.76-1.70 (m, 2H), 0.94-0.90 (t, 3H). LCMS retention time3.526 min; LCMS MH⁺ 509.

Example 24m7-(4-chlorobenzyl)-3-(isoxazol-5-ylmethyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 16 mg, 16.3% yield: ¹H-NMR (DMSO-d₆) δ 8.33-8.31 (d, 2H),7.61-7.57 (t, 1H), 7.45-7.41 (m, 6H), 7.32-7.29 (d, 1H), 5.44 (s, 2H),4.34 (bs, 2H), 3.26 (s, 3H). LCMS retention time 3.114 min; LCMS MH⁺548.

Example 257-(4-chlorobenzyl)-3-(2-(dimethylamino)ethyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 13-(2-bromoethyl)-7-(4-chlorobenzyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.215 mmol) in DMF (3 mL) was added 1,2-dibromoethane (0.2 mL,2.32 mmol), followed by potassium carbonate (60 mg, 0.435 mmol). Themixture was stirred at 50° C. for 16 h. The reaction was partitionedbetween ethyl acetate and water. The organic phase was washed with brineand dried over sodium sulfate, filtered and concentrated to give thecrude product (110 mg, 91.6% yield) as white solid. LCMS retention time2.099 min; LCMS MH⁺ 573.

Step 27-(4-chlorobenzyl)-3-(2-(dimethylamino)ethyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of3-(2-bromoethyl)-7-(4-chlorobenzyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(110 mg, 0.192 mmol) in DMF (3 mL) was added dimethylamine hydrochloride(150 mg, 1.84 mmol), followed by potassium carbonate (100 mg, 0.725mmol). The mixture was stirred at 40° C. for 16 h; then it was dilutedwith ethyl acetate and water. The phases were separated and the organicphase was washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue was purified by preparative HPLC to give7-(4-chlorobenzyl)-3-(2-(dimethylamino)ethyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(15 mg, 13.3% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 9.69 (s, 1H),7.64-7.60 (t, 1H), 7.54 (s, 1H), 7.49-7.43 (m, 5H), 7.35-7.33 (d, 1H),5.47 (s, 2H), 4.21-4.18 (t, 2H), 3.39 (m, 2H), 3.26 (s, 3H), 2.79-2.78(d, 6H). LCMS retention time 3.266 min; LCMS MH⁺558.

Example 267-(4-chlorobenzyl)-1-methyl-3-(2-oxopropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-1-methyl-3-(2-oxopropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(80 mg, 0.153 mmol, example 24j) in ethanol (3 mL) was added sodiumborohydride (12 mg, 0.317 mmol) at 0° C. The resulting mixture wasstirred at 0° C. overnight. The mixture was concentrated and the residuewas purified by preparative HPLC to give the title product (6 mg, 7.47%yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.63-7.58 (t, 1H), 7.50 (s,1H), 7.43-7.41 (m, 5H), 7.33-7.31 (d, 1H), 5.44 (s, 2H), 4.80-4.79 (d,1H), 4.02-3.99 (bs, 1H), 3.89-3.84 (m, 1H), 3.69-3.65 (dd, 1H), 3.24 (s,3H), 1.01-0.99 (d, 3H). LCMS retention time 3.095 min; LCMS MH⁺ 525.

Example 278-(4-chloro-3-(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 18-(4-chloro-3-(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-3-methyl-1-(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-1H-purine-2,6(3H,7H)-dione(150 mg, 0.28 mmol, intermediate 11) in DMF (5 mL) was added4-chloro-3-(trifluoromethyl)phenol (81 mg, 0.45 mmol) and potassiumcarbonate (76 mg, 0.55 mmol). The mixture was stirred at 80° C.overnight. The mixture was partitioned between ethyl acetate and water.The organic phase was washed with brine, dried over sodium sulfate,filtered and concentrated to give a crude product which was used withoutpurification. LCMS retention time 2.112 min; LCMS MH⁺-THP 573.

Step 28-(4-chloro-3-(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of8-(4-chloro-3-(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-3-methyl-1-(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.15 mmol) in ethanol (5 mL) was added acetyl chloride (0.2 mL)at 0° C. The mixture was stirred at room temperature for 1 h. Themixture was partitioned between ethyl acetate and water. The organicphase was dried over sodium sulfate, filtered and concentrated to give acrude product, which was purified via preparative HPLC to give8-(4-chloro-3-(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(37 mg, 43.1% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.95 (d, 1H),7.85 (d, 1H), 7.77-7.80 (m, 1H), 7.44 (s, 4H), 5.44 (s, 2H), 4.58-4.61(m, 1H), 4.06 (t, 2H), 3.59 (t, 2H), 3.43-3.46 (m, 4H), 3.29 (s, 3).LCMS retention time 3.070 min; LCMS MH⁺ 573.

The following examples 28a through 28g were prepared using the method ofexample 27.

Example 28a8-(3,5-bis(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 27 mg, 30.1% yield: ¹H-NMR (DMSO-d₆) δ 8.25 (s, 1H), 8.09(s, 1H), 7.48 (d, 2H), 7.42 (d, 2H), 5.46 (s, 2H), 4.59 (s, 1H), 4.07(t, 2H), 3.57 (t, 2H), 3.40-3.46 (m, 4H), 3.29 (s, 3H). LCMS retentiontime 3.150 min; LCMS MH⁺ 607.

Example 28b7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 30 mg, 40.5% yield: ¹H-NMR (DMSO-d₆) δ 7.78 (s, 1H),7.70-7.73 (m, 3H), 7.44 (s, 4H), 5.45 (s, 2H), 4.59 (t, 1H), 4.06 (t,2H), 3.60 (t, 2H), 3.44 (s, 4H), 3.32 (s, 3H). LCMS retention time 2.923min; LCMS MH⁺ 539.

Example 28c7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(m-tolyloxy)-1H-purine-2,6(3H,7H)-dione

White solid, 21 mg, 29.8% yield: ¹H-NMR (DMSO-d₆) δ 7.37-7.46 (m, 4H),7.33 (t, 1H), 7.09-7.12 (m, 3H), 5.42 (s, 2H), 4.58 (t, 1H), 4.06 (t,2H), 3.56 (t, 2H), 3.45 (t, 4H), 3.32 (s, 3H), 2.32 (d, 3H). LCMSretention time 2.801 min; LCMS MH⁺ 485.

Example 28d7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-8-(3-methoxyphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 26 mg, 37.7% yield: ¹H-NMR (DMSO-d₆) δ 7.38-7.47 (m, 4H),7.36 (t, 1H), 6.88-6.90 (m, 3H), 5.42 (s, 2H), 4.59 (t, 1H), 4.06 (t,2H), 3.76 (s, 3H), 3.56 (t, 2H), 3.45 (s, 4H), 3.29 (s, 3H). LCMSretention time 2.631 min; LCMS MH⁺ 501.

Example 28e7-(4-chlorobenzyl)-8-(3-chlorophenoxy)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 33 mg, 36.8% yield: ¹H-NMR (DMSO-d₆) δ 7.48-7.52 (m, 2H),7.35-7.42 (m, 6H), 5.43 (s, 2H), 4.59 (t, 1H), 4.06 (t, 2H), 3.58 (t,2H), 3.45 (s, 4H), 3.30 (s, 3H). LCMS retention time 2.856 min; LCMS MH⁺505.

Example 28f7-(4-chlorobenzyl)-8-(3-ethylphenoxy)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 27 mg, 36.8% yield: ¹H-NMR (DMSO-d₆) δ 7.36-7.46 (m, 5H),7.11-7.15 (m, 3H), 5.43 (s, 2H), 4.61 (t, 1H), 4.06 (t, 2H), 3.56 (t,2H), 3.43-3.47 (m, 4H), 3.28 (s, 3H), 2.62 (q, 2H), 1.17 (t, 3H). LCMSretention time 2.909 min; LCMS MH⁺ 499.

Example 28g7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(morpholinomethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 41 mg, 41.1% yield: ¹H-NMR (DMSO-d₆) δ 7.77 (s, 1H),7.51-7.58 (m, 2H), 7.43-7.46 (m, 5H), 5.43 (s, 2H), 4.32-4.37 (m, 2H),4.03-4.06 (m, 2H), 3.85-3.90 (m, 4H), 3.54-3.57 (t, 2H), 3.44 (m, 4H),3.27 (s, 3H), 3.00-3.09 (m, 4H). LCMS retention time 1.699 min; LCMS MH⁺570.

Example 297-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-methylbenzyloxy)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-3-methyl-8-(3-methylbenzyloxy)-1-(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-1H-purine-2,6(3H,7H)-dione

To a solution of m-tolylmethanol (37 mg, 0.3 mmol) in DMF (2 mL) wasadded sodium hydride (18 mg, 0.45 mmol) at 0° C. After stirring at 0° C.for 30 min,8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-1H-purine-2,6(3H,7H)-dione(80 mg, 0.15 mmol, intermediate 11) was added. The mixture was stirredat 0° C. for 15 min, then aqueous ammonium chloride solution (2 mL) wasadded at 0° C. The mixture was partitioned between ethyl acetate andwater. The organic layers were combined, dried over sodium sulfate,filtered and concentrated to give a crude product which was used withoutpurification. LCMS retention time 1.967 min; LCMS MH⁺-THP 499.

Step 27-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-methylbenzyloxy)-1H-purine-2,6(3H,7H)-dione

The title product was prepared using the method of example 27, step 2.White solid, 12 mg, 16.2% yield: ¹H-NMR (DMSO-d₆) δ 7.39 (d, 2H),7.25-7.28 (m, 3H), 7.15-7.21 (m, 3H), 5.49 (s, 2H), 5.25 (s, 2H), 4.57(d, 1H), 4.03 (t, 2H), 3.54 (t, 2H), 3.44 (t, 4H), 3.41 (s, 3H). LCMSretention time 2.888 min; LCMS MH⁺ 499.

The following examples 30a through 30d were prepared using the 2 stepmethod of example 29.

Example 30a7-(4-chlorobenzyl)-8-(3-chlorobenzyloxy)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 15 mg, 19.4% yield: ¹H-NMR (DMSO-d₆) δ 7.37-7.44 (m, 6H),7.28 (d, 2H), 5.53 (s, 2H), 5.28 (s, 2H), 4.58 (t, 1H), 4.03 (t, 2H),3.56 (t, 2H), 3.45 (t, 4H), 3.39 (s, 3H). LCMS retention time 2.894 min;LCMS MH⁺ 519.

Example 30b7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethyl)benzyloxy)-1H-purine-2,6(3H,7H)-dione

White solid, 18 mg, 21.6% yield: ¹H-NMR (DMSO-d₆) δ 7.79 (s, 1H), 7.74(d, 2H), 7.63 (t, 1H), 7.37 (d, 2H), 7.28 (d, 2H), 5.62 (s, 2H), 5.28(s, 2H), 4.58 (t, 1H), 4.04 (t, 2H), 3.55 (t, 2H), 3.44-3.45 (m, 4H),3.42 (s, 3H). LCMS retention time 2.921 min; LCMS MH⁺ 553.

Example 30c7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-8-(3-methoxybenzyloxy)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 17 mg, 22.1% yield: ¹H-NMR (DMSO-d₆) δ 7.36-7.38 (m, 2H),7.25-7.32 (m, 3H), 6.91-6.99 (m, 3H), 5.50 (s, 2H), 5.25 (s, 2H), 4.60(t, 1H), 4.03 (t, 2H), 3.73 (s, 3H), 3.54 (t, 2H), 3.42-3.47 (m, 7H).LCMS retention time 2.718 min; LCMS MH⁺ 515.

Example 30d7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethoxy)benzyloxy)-1H-purine-2,6(3H,7H)-dione

White solid, 31 mg, 22.1% yield: ¹H-NMR (DMSO-d₆) δ 7.53 (t, 1H),7.37-7.47 (m, 5H), 7.28 (d, 2H), 5.58 (s, 2H), 5.28 (s, 2H), 4.58 (t,1H), 4.04 (t, 2H), 3.54 (t, 2H), 3.44 (t, 4H), 3.42 (s, 3H). LCMSretention time 2.984 min; LCMS MH⁺ 569.

Example 311-(2-(2-hydroxyethoxy)ethyl)-7-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(50 mg, 0.116 mmol, intermediate 12) in DMF (3 mL) was added1-(bromomethyl)-4-methoxybenzene (35 mg, 0.174 mmol) and potassiumcarbonate (32 g, 0.232 mmol). The reaction was heated at 50° C. for 3 h.The mixture was cooled and partitioned between ethyl acetate and water.The organic layers were combined, dried over sodium sulfate, filteredand concentrated to give a crude product which was purified bypreparative HPLC to give1-(2-(2-hydroxyethoxy)ethyl)-7-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(14 mg, 22.2% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.61 (t, 1H),7.48 (s, 1H), 7.32-7.44 (m, 4H), 6.91 (d, 2H), 5.37 (s, 2H), 4.60 (t,1H), 4.08 (t, 2H), 3.73 (s, 3H), 3.58 (t, 2H), 3.46 (s, 4H), 3.29 (s,3H). LCMS retention time 2.581 min; LCMS MH⁺ 551.

The following products 32a through 32h were prepared using the method ofexample 31.

Example 32a7-(3-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 16 mg, 25.0% yield: ¹H-NMR (400 MHz, DMSO-d₆) δ=7.61 (t,1H), 7.49 (d, 2H), 7.34-7.44 (m, 3H), 7.33 (d, 2H), 5.45 (s, 2H), 4.59(t, 1H), 4.07 (t, 2H), 3.57 (t, 2H), 3.45 (s, 4H), 3.30 (s, 3H). LCMSretention time 2.876 min; LCMS MH⁺ 555.

Example 32b1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-7-(4-methylbenzyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 23 mg, 25.0% yield: ¹H-NMR (DMSO-d₆) δ 7.61 (t, 1H), 7.47(d, 1H), 7.42 (dd, 1H), 7.29-7.34 (m, 3H), 7.16 (d, 2H), 5.77 (s, 2H),4.60 (t, 1H), 4.07 (t, 2H), 3.57 (t, 2H), 3.44-3.47 (m, 4H), 3.30 (s,3H), 2.27 (s, 3H). LCMS retention time 2.750 min; LCMS MH⁺ 535.

Example 32c1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-(4-(trifluoromethyl)benzyl)-1H-purine-2,6(3H,7H)-dione

White solid, 19 mg, 27.9% yield: ¹H-NMR (DMSO-d₆) δ 7.74 (d, 2H), 7.61(t, 3H), 7.44-7.48 (m, 2H), 7.33 (d, 1H) 5.55 (s, 2H), 4.58 (q, 1H),4.09 (t, 2H), 3.56 (t, 2H), 3.45 (s, 4H), 3.31 (s, 3H). LCMS retentiontime 2.831 min; LCMS MH⁺ 589.

Example 32d7-(4-ethylbenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 16 mg, 25.4% yield: ¹H-NMR (DMSO-d₆) δ 7.61 (t, 1H), 7.46(s, 1H), 7.42 (d, 1H), 7.31-7.34 (m, 3H), 7.19 (d, 2H), 5.40 (s, 2H),4.60 (t, 1H), 4.07 (t, 2H), 3.57 (t, 2H), 3.47 (s, 4H), 3.29 (s, 3H),2.57 (q, 2H), 1.14 (t, 3H). LCMS retention time 2.897 min; LCMS MH⁺ 549.

Example 32e1-(2-(2-hydroxyethoxy)ethyl)-7-(3-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 10 mg, 25.0% yield: ¹H-NMR (DMSO-d₆) δ 7.61 (t, 1H), 7.48(s, 1H), 7.40-7.43 (m, 1H), 7.26-7.34 (m, 2H), 6.87-6.98 (m, 3H), 5.41(s, 2H), 4.60 (t, 1H), 4.07 (t, 2H), 3.71 (s, 3H), 3.57 (t, 2H), 3.46(s, 4H), 3.30 (s, 3H). LCMS retention time 2.644 min; LCMS MH⁺ 551.

Example 32f1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-7-(3-methylbenzyl)-8-(3-(trifluoromethoxy)phenoxy).1H-purine-2,6(3H,7H)-dione

White solid, 12 mg, 19.6% yield: ¹H-NMR (DMSO-d₆) δ 7.61 (t, 1H), 7.46(s, 1H), 7.40 (dd, 1H), 7.33 (d, 1H), 7.24 (d, 1H), 7.11-7.19 (m, 3H),5.41 (s, 2H), 4.59 (t, 1H), 4.07 (t, 2H), 3.57 (t, 2H), 3.47 (s, 4H),3.30 (s, 3H), 2.27 (s, 3H). LCMS retention time 2.726 min; LCMS MH⁺ 535.

Example 32g1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-7-(3-(trifluoromethoxy)benzyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 22 mg, 31.4% yield: ¹H-NMR (DMSO-d₆) δ 7.61 (t, 1H), 7.53(t, 1H), 7.41-7.49 (m, 4H), 7.33 (d, 2H), 5.50 (s, 2H), 4.59 (t, 1H),4.07 (t, 2H), 3.56 (t, 2H), 3.46 (s, 4H), 3.30 (s, 3H). LCMS retentiontime 2.865 min; LCMS MH⁺ 605.

Example 32h1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-(3-(trifluoromethyl)benzyl)-1H-purine-2,6(3H,7H)-dione

White solid, 10 mg, 31.4% yield: ¹H-NMR (DMSO-d₆) δ 7.81 (s, 1H),7.58-7.71 (m, 4H), 7.41-7.46 (m, 2H), 7.33 (d, 2H), 5.55 (s, 2H), 4.59(t, 1H), 4.07 (t, 2H), 3.57 (t, 2H), 3.47 (s, 4H), 3.30 (s, 3H). LCMSretention time 2.795 min; LCMS MH⁺ 589.

Example 331-(2-(2-aminoethoxy)ethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 11-(2-(2-bromoethoxy)ethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(120mg, 0.26 mmol, intermediate 9) in DMF (3 mL) was added1-bromo-2-(2-bromoethoxy)ethane (77 mg, 0.33 mmol), potassium carbonate(71 mg, 0.51 mmol). The reaction was heated at 60° C. overnight. Themixture was cooled and partitioned between ethyl acetate and water. Theorganic layers were combined, dried over sodium sulfate, filtered andconcentrated to give crude product (100 mg, 70% of purity by HPLC),which was used without purification. LCMS retention time 2.054 min; LCMSMH⁺ 617

Step 21-(2-(2-aminoethoxy)ethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

1-(2-(2-bromoethoxy)ethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.16 mmol) was dissolved in a preformed solution of ammonia inmethanol (15 mL). The reaction was heated at 60° C. overnight in asealed tube. The reaction was cooled to room temperature and the solventwas evaporated. The residue was purified by preparative HPLC to give1-(2-(2-aminoethoxy)ethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(35mg, 39% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.94 (s, 3H), 7.62 (t,1H), 7.41-7.49 (m, 6H), 7.34 (d, 1H), 5.45 (s, 2H), 4.10 (t, 2H),3.65-3.67 (m, 4H), 3.30 (s, 3H), 2.94 (q, 2H). LCMS retention time 2.323min; LCMS MH⁺ 554.

Example 347-(4-chlorobenzyl)-1-(2-(2-methoxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title product was prepared using the method of example 33, step 1with 2-(2-methoxyethoxy)ethyl methanesulfonate (51 mg, 0.26 mmol,intermediate 34) as the alkylating agent. White solid, 44 mg, 45% yield:¹H-NMR (CD₃OD) δ 7.61 (t, 1H), 7.50 (s, 1H), 7.40-7.45 (m, 5H), 7.33 (d,1H), 5.44 (s, 2H), 4.05 (t, 2H), 3.51-3.57 (m, 4H), 3.36 (s, 2H), 3.29(s, 3H), 3.20 (s, 3H). LCMS retention time 3.161 min; LCMS MH⁺ 569.

Example 357-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(120 mg, 0.257 mmol) in DMF (5 mL) was added 2-bromoethanol (128.9 mg,1.028 mmol) followed by cesium carbonate (167 mg, 0.515 mmol). Theresulting mixture was microwave irradiated at 120° C. for 30 min. Thereaction was partitioned between ethyl acetate and brine. The combinedorganic phase was dried and concentrated to give a residue, which waspurified via preparative HPLC to give7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione(17 mg, 34.7% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.43 (t, 1H),7.27-7.32 (m, 4H), 6.95-7.03 (m, 3H), 5.20 (s, 2H), 4.81 (t, 2H), 4.75(t, 1H), 4.41 (t, 2H), 3.92-3.95 (m, 2H), 3.47-3.52 (m, 2H), 3.31 (s,3H). LCMS retention time 2.731 min; LCMS MH⁺ 555.

Example 367-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of 2-(3-(trifluoromethoxy)phenoxy)ethanol (61 mg, 0.275mmol, intermediate 5) in anhydrous THF (10 mL) was added sodium hydride(66 mg, 2.75 mmol) at 0° C. under a nitrogen atmosphere. The mixture wasstirred at 0° C. for 20 min; then a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(70 mg, 0.137 mmol, intermediate 14) in THF (3 mL) was added dropwise,and the resulting mixture was stirred at 0° C. to room temperature for16 h under nitrogen atmosphere. The mixture was quenched with ice-waterand partitioned between ethyl acetate and brine. The organic layer wasdried over sodium sulfate, filtered and concentrated to give a crudeproduct which was purified via silica gel chromatography eluting withpetroleum ether/ethyl acetate (1:0 to 2:1) to give7-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione(70 mg, 78.2%) as yellow oil. LCMS MH⁺-THP 569.

Step 27-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione(70 mg, 0.107 mmol) in methanol (3 mL) was added concentrated HCl (4drops). The mixture was stirred for 1 h at room temperature. The mixturewas neutralized with saturated sodium bicarbonate, and extracted withethyl acetate. The organic phase was dried over sodium sulfate, filteredand concentrated to give a crude product which was recrystallized fromethanol to give7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione(16 mg, 25.6% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.45-7.41 (t,1H), 7.32-7.27 (m, 4H), 7.03-6.95 (m, 3H), 5.19 (s, 2H), 4.81 (s, 2H),4.49-4.46 (t, 1H), 4.41-4.40 (d, 2H), 3.91-3.88 (t, 2H), 3.44-3.40 (m,5H), 1.69-1.65 (t, 2H). LCMS retention time 3.142 min; LCMS MH⁺ 569.

Example 377-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propoxy)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-8-(3-(3-(trifluoromethoxy)phenoxy)propoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of 3-(3-(trifluoromethoxy)phenoxy)propan-1-ol (95 mg, 0.4mmol, intermediate 35) in THF (5 mL) was added sodium hydride (19 mg,0.40 mmol) at 0° C. After stirred at 0° C. for 30 min,8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-purine-2,6(3H,7H)-dione(0.1g, 0.20 mmol, intermediate 13) was added. The mixture was allowed towarm to room temperature and stirred for 16 h. Then the reaction waschilled to 0° C. and aqueous ammonium chloride solution (2 mL) wasadded. The mixture was partitioned between ethyl acetate and water. Theorganic layer was dried over sodium sulfate, filtered and concentratedto give crude product which was used without purification. LCMS MH⁺-THP569.

Step 27-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propoxy)1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-8-(3-(3-(trifluoromethoxy)phenoxy)propoxy)-1H-purine-2,6(3H,7H)-dione(50 mg, 0.09 mmol,) in ethanol (5 mL) was added acetyl chloride (0.2 mL)at 0° C. The mixture was stirred at room temperature for 1 h; then itwas partitioned between ethyl acetate and water. The organic phase wasseparated and dried over sodium sulfate. This organic layer was thenfiltered and concentrated to give a crude product which was purified bypreparative HPLC to give7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propoxy)1H-purine-2,6(3H,7H)-dione (20 mg, 39.2% yield) as awhite solid. ¹H-NMR (DMSO-d₆) δ 7.40 (t, 1H), 7.28-7.33 (m, 4H), 6.92(dd, 2H), 6.85 (s, 1H), 5.23 (s, 2H), 4.76 (t, 1H), 4.62 (t, 2H), 4.08(t, 2H), 3.93 (t, 2H), 3.49 (q, 2H), 3.33 (s, 3H), 2.18-2.24 (m, 2H).LCMS retention time 3.058 min; LCMS MH⁺ 569.

The following examples 38a through 381 were prepared using the methodsof examples 36 and/or 37.

Example 38a8-(2-(3,5-bis(trifluoromethyl)phenoxy)ethoxy)-7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title product was prepared using intermediate 65. White solid, 49mg, 44.6% yield: ¹H-NMR (DMSO-d₆) δ 7.66 (s, 1H), 7.60 (s, 2H),7.23-7.29 (m, 4H), 5.20 (s, 2H), 4.85 (t, 2H), 4.84 (t, 1H), 4.55-4.57(m, 2H), 3.94 (t, 2H), 3.49 (q, 2H), 3.33 (s, 3H). LCMS retention time3.229 min; LCMS MH⁺ 607.

Example 38b7-(4-chlorobenzyl)-8-(2-(3-chlorophenoxy)ethoxy)-1-(2-hydroxyethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title product was prepared using intermediate 66. White solid, 10mg, 22.2% yield: ¹H-NMR (DMSO-d₆) δ 7.30-7.34 (m, 5H), 7.01-7.04 (m,2H), 6.92-6.94 (m, 1H), 5.19 (s, 2H), 4.74-4.80 (m, 3H), 4.37-4.40 (m,2H), 3.93 (t, 2H), 3.49 (q, 2H), 3.34 (s, 3H). LCMS retention time 2.837min; LCMS MH⁺ 505.

Example 38c7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(2-(m-tolyloxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

The title product was prepared using intermediate 67. White solid, 12mg, 27.9% yield: ¹H-NMR (DMSO-d₆) δ 7.27-7.32 (m, 4H), 7.15-7.19 (m,1H), 6.74-6.79 (m, 3H), 5.19 (s, 2H), 4.74-4.80 (m, 3H), 4.32-4.34 (m,2H), 3.94 (t, 2H), 3.49 (q, 2H), 3.35 (s, 3H), 2.27 (s, 3H). LCMSretention time 2.676 min; LCMS MH⁺ 485.

Example 38d7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(2-(3-(trifluoromethyl)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

The title product was prepared using intermediate 68. White solid, 10mg, 20.8% yield: ¹H-NMR (DMSO-d₆) δ 7.54 (t, 1H), 7.24-7.33 (m, 7H),6.74-6.79 (m, 3H), 5.19 (s, 2H), 4.81-4.83 (m, 2H), 4.75 (t, 1H),4.45-4.46 (m, 2H), 3.94 (t, 2H), 3.49 (q, 2H), 3.35 (s, 3H). LCMSretention time 2.857 min; LCMS MH⁺ 539.

Example 38e8-(2-(4-chloro-3-(trifluoromethyl)phenoxy)ethoxy)-7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title product was prepared using intermediate 71. White solid, 30mg, 49.2% yield: ¹H-NMR (DMSO-d₆) δ 7.64-7.62 (d, 1H), 7.31-7.26 (m,6H), 5.20 (s, 2H), 4.83-4.80 (m, 2H), 4.76-4.73 (t, 1H), 4.46-4.44 (m,2H), 3.95-3.92 (t, 2H), 3.52-3.49 (m, 2H), 3.47 (s, 3H). LCMS retentiontime 2.973 min; LCMS MH⁺ 573

Example 38f7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(2-(2-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

The title product was prepared using intermediate 70. White solid, 18mg, 29.7% yield: ¹H-NMR (DMSO-d₆) δ 7.36-7.34 (d, 2H), 7.29-7.24 (m,5H), 7.07-7.03 (t, 1H), 5.17 (s, 2H), 4.85-4.83 (m, 2H), 4.77-4.74 (t,1H), 4.46-4.44 (m, 2H), 3.95-3.92 (t, 2H), 3.51-3.48 (m, 2H), 3.47 (s,3H). LCMS retention time 2.828 min; LCMS MH⁺ 555.

Example 38g7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(2-(4-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

The title product was prepared using intermediate 69. White solid, 30mg, 49.4% yield: ¹H-NMR (DMSO-d₆) δ 7.32-7.26 (m, 6H), 7.06-7.03 (m,2H), 5.19 (s, 2H), 4.82-4.80 (m, 2H), 4.76-4.73 (t, 1H), 4.38-4.36 (m,2H), 3.95-3.92 (t, 2H), 3.52-3.47 (m, 2H), 3.39 (s, 3H). LCMS retentiontime 2.908 min; LCMS MH⁺ 555.

Example 38h7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenyl)propoxy)-1H-purine-2,6(3H,7H)-dione

The title product was prepared using the methods of examples 36 and 37,and using intermediate 37 in the first step. White solid, 12 mg, 21.4%yield: ¹H-NMR (CD₃OD) δ 7.35-7.49 (m, 5H), 7.07-7.17 (m, 3H), 5.28 (s,2H), 4.54 (t, 2H), 4.10 (t, 2H), 3.67 (t, 2H), 3.45 (s, 2H), 2.75 (t,2H), 2.11-2.18 (m, 2H), 1.83-1.91 (m, 2H). LCMS retention time 3.125min; LCMS MH⁺ 567.

Example 38i7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)benzyloxy)-1H-purine-2,6(3H,7H)-dione

The title product was prepared using the methods of examples 36 and 37,and using 3-trifluoromethoxy-benzyl alcohol in the first step. Whitesolid, 12 mg, 16.0% yield): ¹H-NMR (DMSO-d₆) δ 7.27-7.55 (m, 8H), 5.57(s, 2H), 5.28 (s, 2H), 4.47 (t, 1H), 3.90 (t, 2H), 3.56-3.45 (m, 5H),1.65-1.90 (m, 2H). LCMS retention time 2.870 min; LCMS MH⁺ 539.

Example 38j7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-((5-methylthiazol-2-yl)methoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the methods of examples 36 and 37,and using (5-methylthiazol-2-yl)methanol (intermediate 4, step 1) in thefirst step. White solid, 46 mg, 54.1% yield: ¹H-NMR (CDCl₃) δ 7.50 (d,1H), 7.33-7.32 (m, 2H), 7.26-7.28 (m, 2H), 5.74 (s, 2H), 5.27 (s, 2H),4.19 (t, 2H), 3.61 (t, 1H), 3.51-3.55 (m, 5H), 2.51 (d, 3H), 1.88-1.92(m, 2H). LCMS retention time 2.366 min; LCMS MH⁺ 476.

Example 38k7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-((5-methyloxazol-2-yl)methoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the methods of examples 36 and 37and with (5-methyloxazol-2-yl)methanol (intermediate 40). The crudeproduct was purified via preparative HPLC to give7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-((5-methyloxazol-2-yl)methoxy)-1H-purine-2,6(3H,7H)-dione(17 mg, 40.9%) as white solid. ¹H-NMR (DMSO-d₆) δ 7.38-7.40 (d, 2H),7.26-7.28 (d, 2H), 6.90 (s, 1H), 5.58 (s, 2H), 5.23 (s, 2H), 4.45-4.48(t, 1H), 3.87-3.91 (t, 2H), 3.39-3.44 (t, 2H), 2.28 (s, 3H), 1.65-1.68(m, 2H). LCMS retention time 2.284 min; LCMS MH⁺ 460.

Example 3817-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-((5-methylthiazol-2-yl)methoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the methods of examples 36 and 37and with (5-methyloxazol-2-yl)methanol (intermediate 40). White solid,46 mg, 54.1% yield: ¹H-NMR (DMSO-d₆) δ 7.37-7.39 (d, 2H), 7.26-7.28 (d,2H), 6.90 (s, 1H), 5.58 (s, 2H), 5.23 (s, 2H), 4.73-4.76 (t, 1H),3.93-3.95 (t, 2H), 3.47-3.51 (m, 2H), 3.43 (s, 3H), 2.28 (s, 3H). LCMSretention time 2.194 min; LCMS MH⁺ 446.

Example 397-(4-chlorobenzyl)-8-(2-(3-((dimethylamino)methyl)phenoxy)ethoxy)-1-(2-hydroxyethyl)-3-methyl-1H-purine-2,6(3H,7H)-dionehydrochloride

Step 13-(2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-2,3,6,7-tetrahydro-1H-purin-8-yloxy)ethoxy)benzaldehyde

The title compound was prepared using the method of example 36, step 1and using intermediate 36. The product was purified by silica gelchromatography eluting with petroleum/ethyl acetate (3:1 to 1:1) to give3-(2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-2,3,6,7-tetrahydro-1H-purin-8-yloxy)ethoxy)benzaldehyde(64 mg, 36.4% yield) as yellow syrup. LCMS MH⁺-THP 499.

Step 27-(4-chlorobenzyl)-8-(2-(3-((dimethylamino)methyl)phenoxy)ethoxy)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-purine-2,6(3H,7H)-dione

To a solution of3-(2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-2,3,6,7-tetrahydro-1H-purin-8-yloxy)ethoxy)benzaldehyde(100 mg, 0.171 mmol) in methanol (3 mL) and THF (3 mL) was added aceticacid (0.2 ml, 3.49 mmol) and dimethylamine hydrochloride (90 mg, 1.10mmol). The mixture was stirred at room temperature for 1 h. Then themixture was cooled to 0° C., sodium cyanoborohydride (16.1 mg, 0.256mmol) was added under a nitrogen atmosphere. The resulting mixture wasstirred and allowed to warm to room temperature overnight. The mixturewas concentrated and purified via silica gel chromatography eluting withDCM/methanol (60:1) to give7-(4-chlorobenzyl)-8-(2-(3-((dimethylamino)methyl)phenoxy)ethoxy)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-purine-2,6(3H,7H)-dione(26.1 mg, 24.9%) as white solid. LCMS MH⁺ 613.

Step 37-(4-chlorobenzyl)-8-(2-(3-((dimethylamino)methyl)phenoxy)ethoxy)-1-(2-hydroxyethyl)-3-methyl-1H-purine-2,6(3H,7H)-dionehydrochloride

The title compound was prepared using the method of example 37, step 2to give7-(4-chlorobenzyl)-8-(2-(3-((dimethylamino)methyl)phenoxy)ethoxy)-1-(2-hydroxyethyl)-3-methyl-1H-purine-2,6(3H,7H)-dionehydrochloride (13.6 mg, 65.2% yield) as white solid. ¹H-NMR (DMSO-d₆) δ10.11 (bs, 1H), 7.42-7.38 (t, 1H), 7.33-7.28 (m, 4H), 7.18 (s, 1H),7.11-7.09 (d, 1H), 7.06-7.04 (m, 1H), 5.20 (s, 2H), 4.85-4.83 (m, 2H),4.76-4.73 (t, 1H), 4.39-4.37 (m, 2H), 4.22 (s, 2H), 3.96-3.92 (t, 2H),3.52-3.46 (m, 2H), 3.29 (s, 3H), 2.69 (s, 6H). LCMS retention time 1.678min; LCMS MH⁺ 553.

Example 407-(4-chlorobenzyl)-1-(2-(dimethylamino)ethyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

Step 18-bromo-7-(4-chlorobenzyl)-1-(2-(dimethylamino)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.2 g,0.54 mmol, intermediate 8) in DMF (5 mL) was added2-chloro-N,N-dimethylethanamine (0.87 mg, 0.83 mmol), potassiumcarbonate (0.15 g, 1.08 mmol), and TBAI (2 mg, 0.02 mmol). The reactionwas heated at 80° C. overnight. The mixture was cooled and partitionedbetween ethyl acetate and water. The combined organic layer was driedover sodium sulfate, filtered and concentrated to give a crude product(0.2 g, 84%) as yellow oil, which was used without purification. LCMSMH⁺ 442.

Step 27-(4-chlorobenzyl)-1-(2-(dimethylamino)ethyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 36, step 1and purified by preparative HPLC to give7-(4-chlorobenzyl)-1-(2-(dimethylamino)ethyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione(20 mg, 16.4% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 8.18 (s. 1H),7.43 (t, 1H), 7.26-7.32 (m, 4H), 6.93-7.02 (m, 3H), 5.20 (s, 2H),4.80-4.82 (m, 2H), 4.39-4.41 (m, 2H), 3.99 (t, 2H), 3.67 (s, 3H), 2.58(t, 2H), 2.30 (s, 6H). LCMS retention time 2.352 min; LCMS MH⁺ 582

Example 417-(4-chlorobenzyl)-3-methyl-1-propyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the 2 step method of example 40and purified via preparative HPLC to give7-(4-chlorobenzyl)-3-methyl-1-propyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione(80 mg, 29.7% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.45-7.41 (t,1H), 7.32-7.26 (m, 4H), 7.02-6.94 (m, 3H), 5.19 (s, 2H), 4.82-4.79 (m,2H), 4.41-4.39 (m, 2H), 3.81-3.78 (t, 2H), 1.58-1.49 (m, 2H), 0.86-0.83(t, 3H). LCMS retention time 3.571 min; LCMS MH⁺ 553

Example 427-((5-chloropyridin-2-yl)methyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

Step 17-((5-chloropyridin-2-yl)methyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione(60 mg, 0.14 mmol, intermediate 17) in DMF (5 mL) was added5-chloro-2-(chloromethyl)pyridine (33 mg, 0.20 mmol), potassiumcarbonate (37 mg, 0.27 mmol) and TBAI (2 mg, 0.02 mmol). The reactionwas heated at 50° C. for 8 h. The mixture was cooled and partitionedbetween ethyl acetate and water. The combined organic layer was driedover sodium sulfate, filtered and concentrated to give crude product,which was used without purification. LCMS MH⁺-THP 570.

Step 27-((5-chloropyridin-2-yl)methyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-((5-chloropyridin-2-yl)methyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione(80 mg, 0.14 mmol) in ethanol (5 mL) was added acetyl chloride (0.2 mL)at 0° C. The mixture was stirred at room temperature for 1 h. Themixture was partitioned between ethyl acetate and water. The organicphase was dried over sodium sulfate, filtered and concentrated to givecrude product which was purified by preparative HPLC to give7-((5-chloropyridin-2-yl)methyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione(15 mg, 19.0% yield) as white solid. ¹H-NMR (CD₃OD) δ 8.33 (d, 1H), 7.70(dd, 1H), 7.35 (t, 1H), 7.26 (d, 1H), 6.87 (dd, 1H), 6.76 (s, 1H), 5.43(s, 2H), 4.86-4.87 (m, 2H), 4.33-4.35 (m, 2H), 4.04 (t, 2H), 3.56 (t,2H), 3.54 (s, 3H), 1.80-1.85 (m, 2H). LCMS retention time 2.606 min;LCMS MH⁺ 570.

The following examples 43a through 43e were prepared using the method ofexample 42.

Example 43a1-(3-hydroxypropyl)-3-methyl-7-((6-methylpyridin-3-yl)methyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 20 mg, 26.3% yield: ¹H-NMR (CD₃OD) δ 8.55 (s, 1H), 7.95 (d,1H), 7.39 (dd, 2H), 6.96 (dd, 1H), 6.90 (d, 1H), 6.81 (s, 1H), 5.37 (s,2H), 4.93-4.95 (m, 2H), 4.43-4.45 (m, 2H), 4.07 (t, 2H), 3.61 (t, 2H),3.50 (s, 3H), 2.55 (s, 3H), 1.84-1.88 (m, 2H). LCMS retention time 2.022min; LCMS MH⁺ 550.

Example 43b7-benzyl-1-(3-hydroxypropyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 17 mg, 23.0% yield: ¹H-NMR (DMSO-d₆) δ 7.43 (t, 1H),7.23-7.32 (m, 5H), 6.95-7.04 (m, 3H), 5.20 (s, 2H), 4.80-4.82 (m, 2H),4.70 (t, 1H), 4.40-4.43 (m, 2H), 3.90 (t, 2H), 3.33-3.44 (m, 5H),1.65-1.70 (m, 2H). LCMS retention time 2.897 min; LCMS MH⁺ 535.

Example 43c1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 20 mg, 43.2% yield: ¹H-NMR (CD₃OD) δ 7.39-7.35 (t, 1H),7.28 (s, 1H), 6.93-6.80 (m, 2H), 6.79 (s, 1H), 5.56 (s, 2H), 4.89 (s,2H), 4.39-4.36 (dd, 2H), 4.10-4.06 (t, 2H), 3.61-3.58 (t, 2H), 3.53 (s,3H), 2.35 (s, 3H), 1.90-1.85 (m, 2H). LCMS retention time 2.536 min;LCMS MH⁺ 556.

Example 43d7-ethyl-1-(3-hydroxypropyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 33 mg, 37.1% yield: ¹H-NMR (CD₃OD) δ 7.39 (t, 1H), 7.01(dd, 1H), 6.88-6.90 (m, 2H), 4.87-4.88 (m, 2H), 4.44-4.46 (m, 2H),4.08-4.16 (m, 4H), 3.61 (t, 2H), 3.51 (s, 3H), 1.80-1.90 (m, 2H), 1.32(t, 3H). LCMS retention time 1.526 min; LCMS MH⁺ 473.

Example 43e1-(2-hydroxyethyl)-3,7-dimethyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 16 mg, 50.1% yield: ¹H-NMR (DMSO-d₆) δ 7.41-7.45 (t, 1H),7.04-7.06 (dd, 1H), 6.97-7.00 (m, 2H), 4.75-4.79 (m, 4H), 4.42-4.44 (t,2H), 3.92-3.95 (t, 2H), 3.57 (s, 3H), 3.50-3.52 (t, 2H), 3.47 (s, 3H).LCMS retention time 2.411 min; LCMS MH⁺ 445.

Example 441-(3-hydroxypropyl)-3-methyl-7-((4-methylthiazol-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.25 mmol, intermediate 13) in DMF (5 mL) was added2-(chloromethyl)-4-methylthiazole (47.9 mg, 0.32 mmol, intermediate 54)followed by potassium carbonate (51.6 mg, 0.37 mmol) and a catalyticamount of TBAI. The mixture was stirred at 60° C. for 4 h. The mixturewas diluted with ethyl acetate and extracted with brine and saturatedaqueous ammonium chloride solution. Then the organic phase was dried andconcentrated to give a crude product which was purified by preparativeHPLC to give1-(3-hydroxypropyl)-3-methyl-7-((4-methylthiazol-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(29 mg, 22.7% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.62 (t, 1H),7.41-7.46 (m, 2H), 7.33 (dd, 1H), 7.26 (d, 1H), 5.73 (s, 2H), 4.49 (t,1H), 3.91 (t, 2H), 3.35 (t, 2H), 3.31 (s, 3H), 2.29 (d, 3H), 1.67-1.71(m, 2H). LCMS retention time 2.681 min; LCMS MH⁺ 512.

The following examples 45a through 45m were prepared using the method ofexample 44.

Example 45a1-(3-hydroxypropyl)-3-methyl-7-(thiazol-2-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 42 mg, 38.1% yield: ¹H-NMR (DMSO-d₆) δ 7.74-7.77 (m, 2H)7.62 (t, 1H), 7.41-7.49 (m, 2H), 7.33 (d, 1H), 5.80 (s, 2H), 4.47 (t,1H), 3.91 (t, 2H), 3.43 (t, 2H), 3.31 (s, 3H), 2.29 (d, 3H), 1.65-1.70(m, 2H). LCMS retention time 2.378 min; LCMS MH⁺ 498.

Example 45b1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 22 mg, 28.9% yield: ¹H-NMR (DMSO-d₆) δ 7.70 (s, 1H), 7.63(t, 1H), 7.56 (s, 1H), 7.47-7.50 (m, 1H), 7.34-7.37 (m, 1H), 5.60 (s,2H), 4.50 (t, 1H), 3.95 (t, 2H), 3.46 (t, 2H), 3.30 (s, 3H), 2.59 (s,3H), 1.67-1.74 (m, 2H). LCMS retention time 2.419 min; LCMS MH⁺ 512.

Example 45c7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 23 mg, 30.2% yield: ¹H-NMR (CD₃OD) δ 7.46-7.55 (m, 3H),7.30 (d, 2H), 7.22 (d, 1H), 7.07 (t, 2H), 5.48 (s, 2H), 4.10 (t, 1H),3.60 (t, 2H), 3.40 (s, 3H), 1.84-1.90 (m, 2H). LCMS retention time 2.944min; LCMS MH⁺ 509.

Example 45d1-(3-hydroxypropyl)-3-methyl-7-(4-methylbenzyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 28 mg, 37.3% yield: ¹H-NMR (CD₃OD) δ 7.51 (t, 1H),7.19-7.31 (m, 4H), 7.14 (d, 2H), 5.44 (s, 2H), 4.10 (t, 1H), 3.60 (t,2H), 3.40 (s, 3H), 2.28 (s, 3H), 1.83-1.90 (m, 2H). LCMS retention time3.075 min; LCMS MH⁺ 505.

Example 45e4-((1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-purin-7(6H)-yl)methyl)benzonitrile

White solid, 16 mg, 20.7% yield: ¹H-NMR (CD₃OD) δ 7.72 (d, 2H),7.51-7.59 (m, 3H), 7.32 (d, 2H), 7.22 (d, 1H), 5.58 (s, 2H), 4.08 (t,1H), 3.59 (t, 2H), 3.41 (s, 3H), 1.82-1.87 (m, 2H). LCMS retention time2.750 min; LCMS MH⁺ 516.

Example 45f1-(3-hydroxypropyl)-7-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 22 mg, 28.2% yield: ¹H-NMR (CD₃OD) δ 7.52 (t, 2H), 7.38 (d,2H), 7.20-7.30 (m, 3H), 6.87 (d, 2H), 5.41 (s, 2H), 4.10 (t, 1H), 3.75(s, 3H), 3.60 (t, 2H), 3.40 (s, 3H), 1.83-1.89 (m, 2H). LCMS retentiontime 2.899 min; LCMS MH⁺ 521.

Example 45g1-(3-hydroxypropyl)-3-methyl-7-((6-methylpyridin-3-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 45 mg, 29.7% yield: ¹H-NMR (DMSO-d₆) δ 8.53-8.52 (d, 1H),7.71-7.69 (dd, 1H), 7.63-7.59 (t, 1H), 7.52 (s, 1H), 7.46-7.44 (dd, 1H),7.34-7.32 (d, 1H), 7.25-7.23 (d, 1H), 5.43 (s, 2H), 4.53 (bs, 1H),3.95-3.91 (t, 2H), 3.46-3.43 (t, 2H), 3.28 (s, 3H), 2.43 (s, 3H),1.71-1.68 (m, 2H). LCMS retention time 1.923 min; LCMS MH⁺ 506.

Example 45h7-((5-chloropyridin-2-yl)methyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 49 mg, 37.3% yield: ¹H-NMR (DMSO-d₆) δ 8.54 (s, 1H),7.94-7.97 (dd, 1H), 7.57-7.61 (t, 1H), 7.49-7.51 (d, 1H), 7.38-7.43 (m,2H), 7.30-7.32 (d, 1H), 5.58 (s, 2H), 4.44-4.47 (t, 1H), 3.85-3.89 (t,2H), 3.40-3.42 (t, 2H), 3.30 (s, 3H), 1.63-1.66 (m, 2H). LCMS retentiontime 2.710 min; LCMS MH⁺ 526.

Example 45i7-((6-chloropyridin-3-yl)methyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 20 mg, 22.4% yield: ¹H-NMR (DMSO-d₆) δ 8.50-8.49 (d, 1H),7.90-7.87 (dd, 1H), 7.63-7.58 (t, 1H), 7.54-7.45 (m, 3H), 7.33-7.31 (d,1H), 5.48 (s, 2H), 3.94-3.90 (t, 2H), 3.62-3.59 (t, 2H), 3.28 (s, 3H),1.71-1.67 (t, 2H). LCMS retention time 2.625 min; LCMS MH⁺ 526.

Example 45j7-ethyl-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 40 mg, 54.9% yield: ¹H-NMR (DMSO-d₆) δ 7.64-7.60 (t, 1H),7.55 (s, 1H), 7.47-7.45 (dd, 1H), 7.34-7.32 (d, 1H), 4.25-4.20 (m, 2H),3.95-3.91 (t, 2H), 3.46-3.42 (m, 2H), 3.28 (s, 3H), 1.72-1.68 (m, 2H),1.39-1.35 (t, 3H). LCMS retention time 2.525 min; LCMS MH⁺ 429.

Example 45k1-(3-hydroxypropyl)-3,7-dimethyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 40 mg, 55.1% yield: ¹H-NMR (DMSO-d₆) δ 7.64-7.60 (t, 1H),7.54 (s, 1H), 7.47-7.45 (dd, 1H), 7.32-7.31 (dd, 1H), 4.49-4.46 (t, 1H),3.94-3.90 (t, 2H), 3.78 (s, 3H), 3.46-3.42 (m, 2H), 3.28 (s, 3H),11.73-1.66 (m, 2H). LCMS retention time 2.363 min; LCMS MH⁺ 415.

Example 45l1-(3-hydroxypropyl)-3-methyl-7-((2-methylpyrimidin-5-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Light yellow solid, 18 mg, 20.9% yield: ¹H-NMR (DMSO-d₆) δ 8.76 (s, 2H),7.64-7.58 (m, 2H), 7.50-7.48 (m, 1H), 7.35-7.32 (dd, 1H), 5.45 (s, 2H),3.94-3.91 (t, 2H), 3.46-3.42 (m, 2H), 3.29 (s, 3H), 2.96 (s, 3H),1.71-1.68 (m, 2H). LCMS retention time 2.226 min; LCMS MH⁺ 507.

Example 45m1-(3-hydroxypropyl)-3-methyl-7-((5-methyloxazol-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Light yellow solid, 15 mg, 20.2% yield: ¹H-NMR (DMSO-d₆) δ 7.64-7.60 (t,1H), 7.45-7.40 (m, 2H), 7.34-7.32 (d, 1H), 6.78 (s, 1H), 5.59 (s, 2H),4.50 (bs, 1H), 3.91-3.88 (t, 2H), 3.48 (s, 2H), 3.31 (s, 3H), 2.25 (s,3H), 1.71-1.64 (m, 2H). LCMS retention time 2.358 min; LCMS MH⁺ 496.

Example 467-(4-((dimethylamino)methyl)benzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-(bromomethyl)benzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 44 to give7-(4-(bromomethyl)benzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(126 mg, 43.3% yield) as white solid. LCMS retention time 1.758 min;LCMS MH⁺ 583.

Step 27-(4-((dimethylamino)methyl)benzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 25 step 2and purified via preparative HPLC to give7-(4-((dimethylamino)methyl)benzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(15 mg, 35.3% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 10.94 (s, 1H),7.62-7.57 (m, 3H), 7.50 (s, 1H), 7.46-7.44 (m, 2H), 7.42-7.39 (dd, 1H),7.33-7.31 (d, 1H), 5.48 (s, 2H), 4.25-4.24 (d, 2H), 3.95-3.91 (t, 2H),3.45-3.42 (t, 2H), 3.30 (s, 3H), 2.65-2.64 (d, 6H), 1.71-1.67 (m, 2H).LCMS retention time 3.183 min; LCMS MH⁺ 548.

Example 477-benzyl-3-ethyl-1-(isoxazol-5-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-benzyl-3-ethyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(40 mg, 0.090 mmol, intermediate 47) in DMF (3 mL) was added5-(chloromethyl)isoxazole (30 mg, 0.256 mmol), followed by potassiumcarbonate (50 mg, 0.362 mmol) and TBAI (5 mg, 0.014 mmol). The reactionwas stirred at 60° C. overnight. The mixture was cooled and partitionedbetween ethyl acetate and water. The organic phase was washed withbrine, dried over sodium sulfate, and concentrated to give a crudeproduct, which was purified by preparative HPLC to give7-benzyl-3-ethyl-1-(isoxazol-5-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(5.9 mg, 12.6% yield) as white solid. ¹H-NMR (CD₃OD) δ 8.33-8.32 (d,1H), 7.57-7.53 (t, 1H), 7.47-7.45 (d, 2H), 7.38-7.31 (m, 5H), 7.25-7.23(d, 1H), 6.34-6.33 (dd, 1H), 5.52 (s, 2H), 5.36 (s, 2H), 4.06-4.01 (q,2H), 1.27-1.24 (t, 3H). LCMS retention time 3.269 min; LCMS MH⁺ 528.

Example 487-(4-chloro-3-methoxybenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(300 mg, 0.588 mmol, intermediate 14) in anhydrous DMF (12 mL) was addedprop-2-yn-1-ol (0.15 ml, 2.545 mmol),bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.043 mmol),copper iodide (10 mg, 0.053 mmol) (45 mg, 0.402 mmol) and TEA (3 mL,21.6 mmol). Then the mixture was degassed and refilled with nitrogen 3times. The reaction was stirred at 85° C. overnight under nitrogen. Themixture was cooled, filtered and the filter cake was washed with ethylacetate. The filtrate was concentrated to give a crude product, whichwas purified by silica gel chromatography eluting with DCM/ethyl acetate(3:1 to 1:1) to give7-(4-chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(170 mg, 59.5% yield) as a light yellow solid. LCMS retention time 1.523min; LCMS MH⁺ 487.

Step 27-(4-chlorobenzyl)-8-(3-hydroxypropyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

A solution of7-(4-chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(120 mg, 0.247 mmol) in methanol (15 mL) was degassed and refilled withnitrogen for 3 times; then 10% Pd/C (30 mg) was added. The mixture wasdegassed and refilled with hydrogen 3 times and stirred under 45 psi ofhydrogen at room temperature for 20 min. The mixture was filtered andthe filter cake was washed with methanol. The filtrate was concentratedto give7-(4-chlorobenzyl)-8-(3-hydroxypropyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(100 mg, 82.6% yield) as a grey solid. LCMS retention time 1.447 min;LCMS MH⁺ 491.

Step 37-(4-chlorobenzyl)-8-(3-ethoxypropyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-8-(3-hydroxypropyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.204 mmol) in DMF (3 mL) was added sodium hydride (24.5 mg,0.612 mmol, 60% dispersion in mineral oil) at 0° C. The mixture wasstirred at room temperature for 30 min. Iodoethane (63.6 mg, 0.408 mmol)was added to the reaction and it was stirred at room temperature for 16h. The reaction was partitioned between ethyl acetate and brine. Theorganic phase was dried and concentrated to give a crude product, whichwas purified by silica gel chromatography eluting with petroleumether/ethyl acetate (2:1 to 1:1) to give7-(4-chlorobenzyl)-8-(3-ethoxypropyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(96 mg, 90.6% yield) as a yellow solid. LCMS retention time 1.870 min;LCMS MH⁺ 519.

Step 47-(4-chloro-3-methoxybenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared as example 14, step 3 to give7-(4-chloro-3-methoxybenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(51 mg, 56.5% yield) as a white solid. ¹H-NMR (CD₃OD) δ 7.38-7.35 (d,2H), 7.24-7.22 (d, 2H), 5.62 (s, 2H), 4.12-4.18 (t, 2H), 3.62-3.59 (t,2H), 3.57 (s, 3H), 3.46-3.43 (m, 4H), 2.86-2.82 (t, 2H), 1.98-1.84 (m,4H), 1.18-1.14 (t, 3H). LCMS retention time 2.384 min; LCMS MH⁺ 435.

Example 497-(4-chlorobenzyl)-1,8-bis(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-8-(3-hydroxypropyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(30 mg, 0.061 mmol, example 48, step 3) in ethyl alcohol (20 mL) wasadded acetyl chloride (0.2 mL, 2.80 mmol). The reaction was stirred at0° C. for 10 min. The mixture was concentrated to give a crude product,which was purified by preparative HPLC to give7-(4-chlorobenzyl)-1,8-bis(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(15 mg, 60.6% yield) as a white solid. ¹H-NMR (CD₃OD) δ 7.37-7.35 (d,2H), 7.21-7.22 (d, 2H), 5.62 (s, 2H), 4.11-4.08 (t, 2H), 3.62-3.59 (t,4H), 3.56 (s, 3H), 2.87-2.83 (t, 2H), 1.95-1.83 (m, 4H). LCMS retentiontime 1.801 min; LCMS MH⁺ 407.

Example 508-(cyclopentyloxy)-1-(3-hydroxypropyl)-3-methyl-7-((4-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(GG-000317-120)

To a solution of cyclopentanol (67 mg, 0.78 mmol) in THF (5 mL) wasadded sodium hydride (39 mg, 0.98 mmol) at 0° C. After stirring at 0° C.for 30 min,8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(0.2 g, 0.39 mmol, intermediate 14) was added. The mixture was stirredat room temperature for 16 h; then aqueous ammonium chloride solution (2mL) was added at 0° C. The reaction mixture was partitioned betweenethyl acetate and water. The combined organic layer was dried oversodium sulfate, filtered and concentrated to give a crude solid product.This material was slurried in ice cold ethanol, collected by filtration,and dried under vacuum to give7-(4-chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(180 mg, 89.5% yield) as white solid. LCMS retention time 2.085 min;LCMS MH⁺-THP 433.

Step 28-(cyclopentyloxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(180 mg, 0.35 mmol) in methanol (10 mL) was added ammonium formate (220mg, 3.5 mmol) and 5% Pd/C (20 mg). The reaction was refluxed undernitrogen atmosphere overnight. The mixture was cooled and filtered. Thefiltrate was concentrated to give8-(cyclopentyloxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(120mg, 87.6% yield) as white solid. LCMS retention time 1.345 min; LCMSMH⁺-THP 309.

Step 38-(cyclopentyloxy)-3-methyl-7-((4-methylthiazol-2-yl)methyl)-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-(cyclopentyloxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(0.12 g, 0.31 mmol) in DMF (5 mL) was added2-(chloromethyl)-4-methylthiazole (91 mg, 0.62 mmol, intermediate 54),potassium carbonate (85 mg, 0.62 mmol), and TBAI (2 mg, 0.02 mmol). Thereaction was heated at 50° C. overnight. The mixture was cooled andpartitioned between ethyl acetate and water. The combined organic layerwas dried over sodium sulfate, filtered and concentrated to give a crudeproduct which was used without purification. LCMS retention time 1.704min; LCMS MH⁺-THP 470.

Step 48-(cyclopentyloxy)-1-(3-hydroxypropyl)-3-methyl-7-((4-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 48, step 2to give8-(cyclopentyloxy)-1-(3-hydroxypropyl)-3-methyl-7-((4-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione(60 mg, 60.4% yield) as a white solid. ¹H-NMR (CDCl₃) δ 6.84 (d. 1H),5.55 (s, 2H), 5.46-5.50 (m, 1H), 4.19 (t, 2H), 3.69 (s, 1H), 3.56 (s,3H), 3.52 (s, 2H), 2.42 (d, 3H), 1.87-1.97 (m, 6H), 1.62-1.79 (m, 4H).LCMS retention time 2.163 min; LCMS MH⁺ 420.

The following examples 51a through 51j were prepared following themethod of example 50.

Example 51a7-ethyl-1-(3-hydroxypropyl)-8-isopropoxy-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 50 mg, 58.8% yield: ¹H-NMR (DMSO-d₆) δ 5.15-5.20 (m, 1H),4.46 (t, 1H), 4.02 (q, 2H), 3.90 (t, 2H), 3.42 (q, 2H), 3.34 (s, 3H),1.66-1.70 (m, 2H), 1.38 (d, 6H), 1.25 (t, 3H). LCMS retention time 1.946min; LCMS MH⁺ 311.

Example 51b1-(3-hydroxypropyl)-8-isopropoxy-3-methyl-7-propyl-1H-purine-2,6(3H,7H)-dione

White solid, 39 mg, 44.3% yield: ¹H-NMR (DMSO-d₆) δ 5.15-5.21 (m, 1H),4.46 (t, 1H), 3.95 (t, 2H), 3.90 (t, 2H), 3.41 (q, 2H), 3.37 (s, 3H),1.64-1.71 (m, 4H), 1.37 (d, 6H), 0.81 (t, 3H). LCMS retention time 2.149min; LCMS MH⁺ 325.

Example 51c7-benzyl-1-(3-hydroxypropyl)-8-isopropoxy-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 26 mg, 31.7% yield: ¹H-NMR (CDCl₃) δ 7.40-7.42 (dd, 2H),7.28-7.36 (m, 3H), 5.27 (s, 2H), 4.17-4.20 (t, 2H), 3.77 (m, 1H), 3.51(m, 5H), 1.88-1.92 (m, 2H), 1.43-4.44 (d, 6H). LCMS retention time 2.336min; LCMS MH⁺ 373.

Example 51d1-(3-hydroxypropyl)-8-isopropoxy-3-methyl-7-((6-methylpyridin-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione

White solid, 50 mg, 30.4% yield: ¹H-NMR (DMSO-d₆) δ 8.47 (s, 1H),7.78-7.76 (dd, 1H), 7.31-7.29 (d, 1H), 5.32 (s, 3H), 4.11-4.08 (t, 2H),3.62-3.59 (t, 2H), 3.50 (s, 3H), 2.52 (s, 3H), 1.88-1.85 (m, 2H),1.45-1.44 (d, 6H). LCMS retention time 1.581 min; LCMS MH⁺ 388.

Example 51e8-ethoxy-1-(3-hydroxypropyl)-3-methyl-7-((6-methylpyridin-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione

White solid, 17 mg, 28.7% yield: ¹H-NMR (DMSO-d₆) δ 8.47 (s, 1H),7.75-7.78 (dd, 1H), 7.28-7.30 (d, 1H), 5.32 (s, 3H), 4.58-4.63 (q, 2H),4.07-4.10 (t, 2H), 3.58-3.61 (t, 2H), 3.49 (s, 3H), 2.52 (s, 3H),1.84-1.88 (q, 2H), 1.45-1.48 (t, 3H). LCMS retention time 1.371 min;LCMS MH⁺ 374.

Example 51f8-ethoxy-1-(3-hydroxypropyl)-3-methyl-7-((5-methyloxazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

White solid, 19 mg, 30.6% yield: ¹H-NMR (DMSO-d₆) δ 6.73 (s, 1H), 5.42(s, 2H), 4.57-4.62 (q, 2H), 4.04-4.07 (t, 2H), 3.56-3.59 (t, 2H), 3.53(s, 3H), 2.31 (s, 3H), 1.82-1.86 (q, 2H), 1.40-1.44 (t, 3H). LCMSretention time 1.516 min; LCMS MH⁺ 364.

Example 51g7-((5-chloropyridin-2-yl)methyl)-8-ethoxy-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 13 mg, 31.2% yield: ¹H-NMR (CDCl₃) δ 8.49 (s, 1H),7.64-7.66 (dd, 1H), 7.20-7.22 (d, 1H), 5.40 (s, 2H), 4.55-4.60 (q, 2H),4.14-4.16 (t, 2H), 3.59-3.61 (t, 1H), 3.56 (s, 3H), 3.46-3.49 (t, 3H),1.86-1.88 (m, 2H), 1.40-1.42 (t, 2H). LCMS retention time 1.896 min;LCMS MH⁺ 394.

Example 51h8-(cyclopentylmethoxy)-7-ethyl-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Light yellow solid, 11 mg, 20.7% yield: ¹H-NMR (DMSO-d₆) δ 4.45-4.35 (t,1H), 4.35-4.33 (d, 2H), 4.07-4.02 (m, 2H), 3.92-3.88 (t, 2H), 3.45-3.40(q, 2H), 3.30 (s, 3H), 2.39-2.32 (m, 1H), 1.80-1.52 (m, 8H), 1.37-1.24(m, 5H). LCMS retention time 2.485 min; LCMS MH⁺ 351.

Example 51i8-(cyclopentylmethoxy)-1-(3-hydroxypropyl)-3-methyl-7-propyl-1H-purine-2,6(3H,7H)-dione

White solid, 16 mg, 31.5% yield: ¹H-NMR (DMSO-d₆) δ 4.45-4.34 (t, 1H),4.35-4.33 (d, 2H), 3.99-3.96 (t, 2H), 3.91-3.88 (t, 2H), 3.44-3.40 (m,2H), 3.37 (s, 3H), 2.37-2.34 (m, 1H), 1.78-1.52 (m, 8H), 1.35-1.31 (m,2H), 0.84-0.80 (t, 3H). LCMS retention time 2.670 min; LCMS MH⁺ 365.

Example 51j8-(cyclopentylmethoxy)-1-(3-hydroxypropyl)-3-methyl-7-((6-methylpyridin-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione

White solid, 25 mg, 49.9% yield: ¹H-NMR (DMSO-d₆) δ 8.43 (s, 1H),7.61-7.58 (dd, 1H), 7.24-7.22 (d, 1H), 5.22 (s, 2H), 4.47-4.44 (t, 1H),4.35-4.34 (d, 2H), 3.93-3.89 (t, 2H), 3.45-3.38 (m, 2H), 3.35 (s, 3H),2.33 (s, 3H), 2.13-2.11 (m, 1H), 1.70-1.51 (m, 8H), 1.28-1.25 (m, 2H).LCMS retention time 1.761 min; LCMS MH⁺ 428.

Example 527-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dionehydrochloride

Step 17-(4-chlorobenzyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.195 mmol, intermediate 14) in in DMF (5 mL) was added6-methylpyridin-3-ol (24 mg, 0.22 mmol) followed by potassium carbonate(76 mg, 0.55 mmol) and the mixture was stirred at 85° C. for 3 h. Themixture was cooled and partitioned between ethyl acetate and brine. Thelayers were separated and the organic layer was washed with saturatedaqueous ammonium chloride, dried and concentrated to give7-(4-chlorobenzyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(79 mg, 75% yield) as yellow solid. LCMS retention time 2.297 min; LCMSMH⁺-THP 456.

Step 27-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione

A solution of7-(4-chlorobenzyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(79 mg, 0.146 mmol) in 1N ethanolic HCl (3 mL) was stirred at roomtemperature for 2 h. The mixture was concentrated to dryness to give acrude product, which was purified via preparative HPLC to give7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione(35 mg, 52.6% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 8.69 (s, 1H),8.03-8.01 (d, 1H), 7.59-7.57 (d, 1H), 7.45 (s, 4H), 5.45 (s, 2H),4.06-3.98 (m, 2H), 3.45-3.42 (t, 2H), 3.28 (s, 3H), 2.59 (s, 3H),1.71-1.67 (t, 2H). LCMS retention time 2.207 min; LCMS MH⁺ 456.

The following examples 53a and 53b were prepared using the method ofexample 52.

Example 53a7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-methylpyridin-4-yloxy)-1H-purine-2,6(3H,7H)-dionehydrochloride

White solid, isolated as the HCl salt, 30 mg, 36.6% yield: ¹H-NMR(DMSO-d₆) δ 8.48-8.46 (d, 1H), 8.17 (s, 1H), 7.43-7.33 (m, 4H),7.26-7.22 (m, 2H), 5.42 (s, 2H), 4.52 (s, 1H), 3.95-3.92 (t, 2H),3.44-3.42 (m, 2H), 3.37 (s, 3H), 2.47 (s, 3H), 1.72-1.69 (t, 2H). LCMSretention time 1.716 min; LCMS MH⁺ 456.

Example 53b7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(5-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione

White solid, 40 mg, 48.8% yield: ¹H-NMR (DMSO-d₆) δ 8.45-8.44 (d, 1H),8.36 (s, 1H), 7.65 (s, 1H), 7.46-7.41 (m, 4H), 5.44 (s, 2H), 4.50-4.47(t, 1H), 3.94-3.91 (t, 2H), 3.46-3.40 (m, 2H), 3.28 (s, 3H), 2.34 (s,3H), 1.73-1.66 (m, 2H). LCMS retention time 2.259 min; LCMS MH⁺ 456.

Example 547-butyl-1-(3-hydroxypropyl)-3-methyl-8-(5-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione

Step 13-methyl-8-(5-methylpyridin-3-yloxy)-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 52, step 1from intermediate 16, step 1 to give3-methyl-8-(5-methylpyridin-3-yloxy)-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(300 mg, 97.6% yield) as yellow oil. LCMS retention time 1.838 min; LCMSM-THP+H 462.

Step 27-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione

To a solution of3-methyl-8-(5-methylpyridin-3-yloxy)-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(300 mg, 0.554 mmol) in ethyl alcohol (10 mL) was added concentrated HCl(3 mL) and the mixture was stirred for 6 h at reflux. The mixture wascooled, concentrated and filtered to give7-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione(159 mg, 86.6% yield) as yellow solid. LCMS retention time 0.356 min;LCMS MH⁺ 332.

Step 37-butyl-1-(3-hydroxypropyl)-3-methyl-8-(5-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 44, step 3to give7-butyl-1-(3-hydroxypropyl)-3-methyl-8-(5-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione(30 mg, 42.8% yield) as white solid. ¹H-NMR (DMSO-d₆)=8.48-8.47 (d, 1H),8.37-8.36 (d, 1H), 7.71 (s, 1H), 4.51-4.48 (t, 1H), 4.22-4.19 (t, 2H),3.94-3.91 (t, 2H), 3.46-3.43 (t, 2H), 3.28 (s, 3H), 2.36 (s, 3H),1.81-1.66 (m, 4H), 1.35-1.30 (m, 2H), 0.93-0.89 (t, 3H). LCMS retentiontime 1.854 min; LCMS MH⁺ 388.

Example 558-(3-fluorophenoxy)-1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione(50 mg, 0.12 mmol, intermediate 16) in DMF (3 mL) was added3-fluorophenol (23 mg, 0.17 mmol) and potassium carbonate (75 g, 0.24mmol). The mixture was stirred at 80° C. for 12 h. The mixture wascooled and partitioned between ethyl acetate and water. The organicphase was washed with brine, dried over sodium sulfate, filtered andconcentrated to give a crude product which was purified by preparativeHPLC to give8-(3-fluorophenoxy)-1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione(11 mg, 20.75% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.42-7.48 (m,2H), 7.18-7.22 (m, 2H), 7.06-7.10 (m, 1H), 5.76 (s, 2H), 4.10 (t, 2H),3.61 (t, 2H), 3.45 (s, 3H), 2.47 (d, 3H), 1.85-1.90 (m, 2H). LCMSretention time 1.273 min; LCMS MH⁺ 446.

The following examples 56a through 56i were prepared using the method ofexample 55.

Example 56a8-(3-chlorophenoxy)-1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

White solid, 17 mg, 30.9% yield: ¹H-NMR (CD₃OD) δ 7.42-7.47 (m, 3H),7.30-7.35 (m, 2H), 5.76 (s, 2H), 4.10 (t, 2H), 3.61 (t, 2H), 3.44 (s,3H), 2.48 (d, 3H), 1.85-1.90 (m, 2H). LCMS retention time 2.246 min;LCMS MH⁺ 462.

Example 56b1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-8-(m-tolyloxy)-1H-purine-2,6(3H,7H)-dione

White solid, 25 mg, 47.1% yield: ¹H-NMR (CD₃OD) δ 7.42 (d, 1H),7.29-7.34 (m, 1H), 7.09-7.13 (m, 3H), 5.75 (s, 2H), 4.10 (t, 2H), 3.61(t, 2H), 3.43 (s, 3H), 2.48 (d, 3H), 2.38 (s, 3H), 1.84-1.91 (m, 2H).LCMS retention time 2.199 min; LCMS MH⁺ 442.

Example 56c1-(3-hydroxypropyl)-8-(3-methoxyphenoxy)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

White solid, 18 mg, 47.1% yield: ¹H-NMR (CD₃OD) δ 7.41 (d, 1H), 7.33 (t,1H), 6.85-6.91 (m, 3H), 5.74 (s, 2H), 4.09 (t, 2H), 3.81 (s, 3H), 3.61(t, 2H), 3.43 (s, 3H), 2.47 (d, 3H), 1.84-1.90 (m, 2H). LCMS retentiontime 2.092 min; LCMS MH⁺ 458.

Example 56d1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 45 mg, 47.1% yield: ¹H-NMR (CD₃OD) δ 7.64-7.71 (m, 4H),7.41 (d, 1H), 5.78 (s, 2H), 4.10 (t, 2H), 3.61 (t, 2H), 3.45 (s, 3H),2.47 (d, 3H), 1.85-1.91 (m, 2H). LCMS retention time 2.349 min; LCMS MH⁺496.

Example 56e8-(4-fluorophenoxy)-1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

White solid, 23 mg, 43.4% yield: ¹H-NMR (CD₃OD) δ 7.42 (d, 1H),7.35-7.39 (m, 2H), 7.17-7.22 (m, 2H), 5.76 (s, 2H), 4.10 (t, 2H), 3.61(t, 2H), 3.45 (s, 3H), 2.48 (d, 3H), 1.85-1.90 (m, 2H). LCMS retentiontime 2.108 min; LCMS MH⁺ 446.

Example 56f1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-8-(4-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 20 mg, 40.4% yield: ¹H-NMR (CD₃OD) δ 7.78 (d, 2H), 7.57 (d,2H), 7.41 (d, 1H), 5.78 (s, 2H), 4.10 (t, 2H), 3.61 (t, 2H), 3.45 (s,3H), 2.48 (d, 3H), 1.85-1.90 (m, 2H). LCMS retention time 2.386 min;LCMS MH⁺ 496.

Example 56g1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-8-(4-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 19 mg, 31.1% yield: ¹H-NMR (CD₃OD) δ 7.46-7.49 (m, 2H),7.38-7.42 (m, 3H), 5.77 (s, 2H), 4.10 (t, 2H), 3.61 (t, 2H), 3.44 (s,3H), 2.47 (s, 3H), 1.85-1.90 (m, 2H). LCMS retention time 2.432 min;LCMS MH⁺ 512.

Example 56h8-(4-chlorophenoxy)-1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

White solid, 15 mg, 31.1% yield: ¹H-NMR (CD₃OD) δ 7.42-7.48 (m, 3H),7.35-7.38 (m, 2H), 5.76 (s, 2H), 4.10 (t, 2H), 3.61 (t, 2H), 3.43 (s,3H), 2.48 (d, 3H), 1.85-1.91 (m, 2H). LCMS retention time 2.273 min;LCMS MH⁺ 462.

Example 56i1-(3-hydroxypropyl)-8-(4-methoxyphenoxy)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

White solid, 13 mg, 31.1% yield: ¹H-NMR (CD₃OD) δ 7.42 (d, 1H), 7.23(dd, 2H), 6.98 (dd, 2H), 5.74 (s, 2H), 4.09 (t, 2H), 3.82 (s, 3H), 3.60(t, 2H), 3.42 (s, 3H), 2.48 (d, 3H), 1.85-1.90 (m, 2H). LCMS retentiontime 2.104 min; LCMS MH⁺ 458.

Example 578-ethoxy-1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione(50 mg, 0.12 mmol, intermediate 16) in ethanol (2 mL) was added sodium(10 mg, 0.4 mmol). The mixture was stirred at room temperature for 2 h.The reaction was concentrated and the residue was purified bypreparative HPLC to give8-ethoxy-1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione(27 mg, 59.3%) as white solid. ¹H-NMR (CD₃OD) δ 7.38 (d, 1H), 5.55 (s,2H), 4.60 (q, 2H), 4.09 (t, 2H), 3.59 (t, 2H), 3.52 (s, 3H), 2.45 (d,3H), 1.83-1.88 (m, 2H), 1.43 (d, 3H). LCMS retention time 1.680 min;LCMS MH⁺ 380.

Example 587-ethyl-1-(3-hydroxypropyl)-3-methyl-8-((5-methylthiazol-2-yl)methoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the 2 step method of example 36from intermediate 6. The product was purified via preparative HPLC togive7-ethyl-1-(3-hydroxypropyl)-3-methyl-8-((5-methylthiazol-2-yl)methoxy)-1H-purine-2,6(3H,7H)-dione(5 mg, 6.9% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.53 (s, 1H), 5.76(s, 2H), 4.18 (q, 2H), 4.10 (t, 2H), 3.61 (t, 2H), 3.54 (s, 3H), 2.52(s, 3H), 1.80-1.90 (m, 2H), 1.36 (t, 3H). LCMS retention time 1.760 min;LCMS MH⁺ 380.

Example 597-benzyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 17-benzyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-benzyl-8-chloro-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(4.7 g, 8.58 mmol, intermediate 18) in DMF (15 mL) was added3-(trifluoromethoxy)phenol (1.83 g, 10.28 mmol) and potassium carbonate(2.4 g, 17.39 mmol). The mixture was stirred at 80° C. overnight. Themixture was diluted with ethyl acetate and water, and the phases wereseparated. The organic phase was washed with brine, dried over sodiumsulfate, filtered and concentrated to give7-benzyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(5.3 g, 89.3% yield) as yellow oil. LCMS retention time 3.974 min; LCMSM+Na 713.

Step 27-benzyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-benzyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(5.3 g, 7.68 mmol) in ethyl alcohol (20 mL) was added concentrated HCl(5 mL). The reaction was stirred at 80° C. overnight. The reaction wasconcentrated and the residue was neutralized with saturated sodiumbicarbonate. This aqueous phase was extracted with ethyl acetate and thephases were separated. The organic phase was washed with brine, driedover sodium sulfate, filtered and concentrated to give7-benzyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(4.5 g, 100% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 11.93 (s, 1H),7.62-7.57 (t, 1H), 7.44-7.32 (m, 8H), 5.42 (s, 2H), 4.49-4.46 (t, 1H),3.89-3.86 (t, 2H), 3.46-3.41 (m, 2H), 1.72-1.65 (m, 2H). LCMS retentiontime 2.560 min; LCMS MH⁺ 477.

Example 607-benzyl-3-ethyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-benzyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(1.2 g, 2.52 mmol, example 59) in DMF (5 mL) was added iodoethane (0.7g, 4.49 mmol), followed by potassium carbonate (0.7 g, 5.07 mmol). Thereaction was stirred at 80° C. for 2 h; then it was cooled andpartitioned between ethyl acetate and water. The phases were separatedand the organic phase was washed with brine. The organic layer was driedover sodium sulfate, filtered and concentrated to give7-benzyl-3-ethyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.62 g, 49.2% yield) as yellow solid. ¹H-NMR (DMSO-d₆) δ 7.62-7.57 (t,1H), 7.50 (s, 1H), 7.42-7.31 (m, 7H), 5.44 (s, 2H), 4.51-4.48 (t, 1H),3.95-3.85 (m, 4H), 3.47-3.42 (q, 2H), 1.73-1.67 (m, 2H), 1.16-1.13 (t,3H). LCMS retention time 2.974 min; LCMS MH⁺ 505.

Example 613-ethyl-1-(3-hydroxypropyl)-7-((6-methylpyridin-3-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 13-ethyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

7-benzyl-3-ethyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.62 g, 1.23 mmol, example 60) was dissolved in ethanol (20 mL); thenthe mixture was degassed and refilled with nitrogen three times.Ammonium formate (0.5 g, 7.94 mmol) and 10% Pd/C (30 mg) were added. Themixture was again degassed and refilled with nitrogen three times; thenit was stirred at 80° C. overnight. The reaction was cooled andfiltered. The filter cake was washed with methanol. The filtrate wasconcentrated to give3-ethyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.6 g, 100% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.61-7.57 (t,1H), 7.50 (s, 1H), 7.40-7.38 (dd, 1H), 7.31-7.29 (d, 1H), 4.50 (s, 1H),3.95-3.85 (m, 4H), 3.44-3.43 (m, 2H), 1.73-1.66 (t, 2H), 1.17-1.13 (t,3H). LCMS retention time 1.350 min; LCMS MH⁺ 415.

Step 23-ethyl-1-(3-hydroxypropyl)-7-((6-methylpyridin-3-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of3-ethyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(110 mg, 0.22 mmol) in DMF (3 mL) was added5-(chloromethyl)-2-methylpyridine (50 mg, 0.4 mmol), potassium carbonate(91 mg, 0.66 mmol), and TBAI (2 mg, 0.02 mmol). The reaction was heatedat 50° C. overnight. The mixture was cooled and partitioned betweenethyl acetate and water. The combined organic layer was dried oversodium sulfate, filtered and concentrated to give a crude product, whichwas purified by preparative HPLC to give3-ethyl-1-(3-hydroxypropyl)-7-((6-methylpyridin-3-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(30 mg, 44.8% yield) as a white solid. ¹H-NMR (DMSO-d₆) δ 8.53 (d, 1H),7.71 (dd, 1H), 7.55-7.63 (m, 2H), 7.50 (dd, 1H), 7.32 (d, 1H), 7.25 (d,1H), 5.43 (s, 2H), 4.48 (t, 1H), 3.85-3.96 (m, 4H), 3.44 (q, 2H), 2.44(s, 3H), 1.68-1.73 (m, 2H), 1.14 (t, 3H). LCMS retention time 2.097 min;LCMS MH⁺ 520.

The following examples 62a through 62d were prepared using the method ofexample 61.

Example 62a7-((5-chloropyridin-2-yl)methyl)-3-ethyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 30 mg, 28.1% yield: ¹H-NMR (DMSO-d₆) δ 8.47 (s, 1H),7.84-7.87 (dd, 1H), 7.53-7.57 (t, 1H), 7.46-7.48 (d, 1H), 7.34-7.39 (m,2H), 7.22-7.24 (d, 1H), 5.63 (s, 2H), 4.03-4.08 (m, 4H), 3.56-3.59 (t,2H), 1.82-1.85 (q, 2H), 1.26-1.29 (t, 3H). LCMS retention time 2.701min; LCMS MH⁺ 540.

Example 62b7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 15 mg, 20.1% yield: ¹H-NMR (DMSO-d₆) δ 7.60-7.56 (t, 1H),7.49 (s, 1H), 7.43-7.39 (m, 5H), 7.30-7.28 (d, 1H), 5.40 (s, 2H), 4.49(bs, 1H), 3.92-3.82 (m, 4H), 3.43-3.36 (m, 2H), 1.71-1.64 (m, 2H),1.14-1.10 (t, 3H). LCMS retention time 1.906 min; LCMS MH⁺ 539.

Example 62c3,7-diethyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 15 mg, 20.1% yield: ¹H-NMR (DMSO-d₆) δ 7.64-7.57 (m, 2H),7.47-7.45 (dd, 1H), 7.34-7.32 (d, 1H), 4.49-4.47 (t, 1H), 4.25-4.20 (q,2H), 3.96-3.85 (m, 4H), 3.47-3.38 (m, 2H), 1.74-1.67 (m, 2H), 1.39-1.36(t, 3H), 1.16-1.13 (t, 3H). LCMS retention time 2.667 min; LCMS MH⁺ 443.

Example 62d3-ethyl-1-(3-hydroxypropyl)-7-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

White solid, 15 mg, 14.2% yield: ¹H-NMR (DMSO-d₆) δ 7.64-7.59 (t, 1H),7.56 (s, 1H), 7.47-7.44 (dd, 1H), 7.33-7.31 (d, 1H), 4.50-4.48 (t, 1H),3.95-3.84 (m, 4H), 3.46-3.42 (m, 2H), 1.73-1.66 (m, 2H), 1.15-1.12 (t,3H). LCMS retention time 2.504 min; LCMS MH⁺ 429.

Example 631-(3-hydroxypropyl)-7-((6-methylpyridin-3-yl)methyl)-3-propyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 11-(3-hydroxypropyl)-3-propyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the methods of examples 60 and 61,step 1 from the product of example 59. White solid, 180 mg, 70.1% yield:LCMS retention time 1.452 min; LCMS MH⁺ 429.

Step 21-(3-hydroxypropyl)-7-((6-methylpyridin-3-yl)methyl)-3-propyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 61, step 2.The product was purified via preparative HPLC to give1-(3-hydroxypropyl)-7-((6-methylpyridin-3-yl)methyl)-3-propyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(7.1 mg, 15.1% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 8.53-8.52 (d,1H), 7.72-7.68 (dd, 1H), 7.63-7.56 (m, 2H), 7.45-7.42 (dd, 1H),7.33-7.31 (dd, 1H), 7.26-7.24 (d, 1H), 5.42 (s, 2H), 4.50-4.47 (t, 1H),3.95-3.91 (t, 2H), 3.82-3.78 (t, 2H), 3.46-3.42 (q, 2H), 2.44 (s, 3H),1.73-1.58 (m, 4H), 0.82-0.78 (t, 3H). LCMS retention time 2.276 min;LCMS MH⁺ 534.

Example 647-(4-chlorobenzyl)-8-(3-((dimethylamino)methyl)phenoxy)-1-(3-hydroxypropyl)-3-propyl-1H-purine-2,6(3H,7H)-dione

Step 18-chloro-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-propyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 60. Whitesolid, 160 mg, 72.3% yield: LCMS retention time 1.574 min; LCMS MH⁺ 411.

Step 33-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-8-yloxy)benzaldehyde

The title compound was prepared using the method of example 59, step 1.Yellow oil, 190 mg, 70.9% yield: LCMS retention time 1.663 min; LCMS MH⁺497.

Step 47-(4-chlorobenzyl)-8-(3-((dimethylamino)methyl)phenoxy)-1-(3-hydroxypropyl)-3-propyl-1H-purine-2,6(3H,7H)-dionehydrochloride

The title product was prepared using the method of example 39, step 2and the crude product was purified by preparative HPLC. White solid, 15mg, 14.3%: ¹H-NMR (DMSO-d₆) δ 11.04 (bs, 1H), 7.60 (bs, 1H), 7.57-7.49(m, 2H), 7.46-7.41 (m, 5H), 5.43 (s, 2H), 4.29-4.28 (d, 2H), 3.95-3.91(t, 2H), 3.81-3.77 (t, 2H), 3.45-3.42 (t, 2H), 2.68-2.67 (d, 6H),1.72-1.66 (m, 2H), 1.63-1.54 (m, 2H), 0.81-0.77 (t, 3H). LCMS retentiontime 1.755 min; LCMS MH⁺ 526.

Example 657-(4-chlorobenzyl)-8-(3-((dimethylamino)methyl)phenoxy)-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dionehydrochloride

The title compound was prepared using the method of example 64. Whitesolid, 13 mg, 14.5% yield: ¹H-NMR (DMSO-d₆) δ 11.15 (s, 1H), 7.63 (s,1H), 7.58-7.50 (m, 2H), 7.47-7.42 (m, 5H), 5.43 (s, 2H), 4.31-4.29 (d,2H), 3.95-3.91 (t, 2H), 3.89-3.83 (m, 2H), 3.46-3.42 (t, 2H), 2.69-2.67(d, 6H), 1.73-1.66 (m, 2H), 1.15-1.11 (t, 3H). LCMS retention time 1.668min; LCMS MH⁺ 512.

Example 667-(4-chlorobenzyl)-8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (70 mg,0.248 mmol, intermediate 26) in DMF (3 mL) was added1-(bromomethyl)-4-chlorobenzene (80 mg, 0.390 mmol), followed bypotassium carbonate (60 mg, 0.435 mmol). The mixture was stirred at 60°C. for 4 h, then diluted with ethyl acetate and water, and the phaseswere separated. The organic phase was washed with brine, dried oversodium sulfate, filtered and concentrated to give a crude product whichwas purified by preparative HPLC to give7-(4-chlorobenzyl)-8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione(15 mg, 14.9% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.43-7.41 (d,2H), 7.34-7.32 (d, 2H), 5.21 (s, 2H), 4.53-4.44 (m, 3H), 3.99-3.88 (m,4H), 3.45-3.39 (m, 2H), 1.71-1.64 (m, 2H), 1.37-1.33 (t, 3H), 1.23-1.19(t, 3H). LCMS retention time 2.654 min; LCMS MH⁺ 407.

Example 677-(4-chlorobenzyl)-8-ethoxy-1-(3-hydroxypropyl)-3-propyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the methods of intermediate 26 andexample 66. White solid, 5 mg, 17.0% yield: ¹H-NMR (DMSO-d₆) δ 7.43-7.42(d, 2H), 7.33-7.31 (d, 2H), 5.21 (s, 2H), 4.52-4.47 (m, 3H), 3.92-3.87(m, 4H), 3.44-3.41 (m, 2H), 1.72-1.63 (m, 4H), 1.36-1.33 (t, 3H),0.88-0.84 (t, 3H). LCMS retention time 2.837 min; LCMS MH⁺ 421.

Example 687-(4-chlorobenzyl)-8-(2-ethoxyethoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the two-step method of example 36.White solid, 33 mg, 26.2% yield: ¹H-NMR (DMSO-d₆) δ 7.34-7.41 (m, 4H),5.21 (s, 2H), 4.58 (t, 2H), 4.47 (t, 1H), 3.90 (t, 2H), 3.69-3.72 (m,2H), 3.41-3.47 (m, 7H), 1.65-1.70 (m, 2H), 1.08 (t, 3H). LCMS retentiontime 2.423 min; LCMS MH⁺ 437.

Example 697-(4-chlorobenzyl)-8-(isopropylsulfonyl)-1-(isoxazol-5-ylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-8-(isopropylthio)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.2 g,0.54 mmol, intermediate 8) in DMF (5 mL) was added propane-2-thiol (0.2g, 2.7 mmol) and potassium carbonate (0.38 g, 2.7 mmol). The reactionwas heated at 80° C. overnight. The mixture was cooled and partitionedbetween ethyl acetate and water. The organic phase was dried over sodiumsulfate, filtered and concentrated to give a crude product (0.2 g) whichwas used without purification. LCMS retention time 1.015 min; LCMS MH⁺365.

Step 27-(4-chlorobenzyl)-8-(isopropylsulfonyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-8-(isopropylthio)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.2 g, 0.55 mmol) in chloroform (10 mL) was added MCPBA (0.19 g, 1.37mmol) portionwise at 0° C. The reaction was stirred at room temperatureovernight. The mixture was partitioned between ethyl acetate and water.The combined organic layer was dried over sodium sulfate, filtered andconcentrated to give a crude solid product which was triturated inethanol and collected to afford7-(4-chlorobenzyl)-8-(isopropylsulfonyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.19 g, 84.5% yield) as a white solid. LCMS retention time 1.322 min;LCMS MH⁺ 397.

Step 37-(4-chlorobenzyl)-8-(isopropylsulfonyl)-1-(isoxazol-5-ylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-8-(isopropylsulfonyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(80 mg, 0.20 mmol) in DMF (5 mL) was added 5-(chloromethyl)isoxazole (55mg, 0.5 mmol, intermediate 41), potassium carbonate (58 mg, 0.42 mmol),and TBAI (2 mg, 0.02 mmol). The reaction was heated at 50° C. overnight.The mixture was cooled and partitioned between ethyl acetate and water.The combined organic layer was dried over sodium sulfate, filtered andconcentrated to give a crude product which was purified by preparativeHPLC to give7-(4-chlorobenzyl)-8-(isopropylsulfonyl)-1-(isoxazol-5-ylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(39 mg, 40.6% yield) as a white solid. ¹H-NMR (CD₃OD) δ 8.49 (d, 1H),7.41 (dd, 2H), 7.28 (d, 2H), 6.43 (d, 1H), 5.87 (s, 2H), 5.21 (s, 2H),3.60-3.73 (m, 1H), 3.47 (s, 3H), 1.25 (d, 6H). LCMS retention time 2.772min; LCMS MH⁺ 478

Example 707-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(methylsulfonyl)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-3-methyl-8-(methylthio)-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(0.15 g, 0.35 mmol, intermediate 14) was dissolved in sodiumthiomethoxide (5 mL). The reaction was heated at 80° C. overnight. Themixture was cooled and partitioned between ethyl acetate and water. Thecombined organic layer was dried over sodium sulfate, filtered andconcentrated to give a crude product which was used withoutpurification. LCMS retention time 1.875 min; LCMS MH⁺-THP 395.

Step 27-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(methylsulfonyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-8-(methylthio)-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(0.14 g, 0.35 mmol) in chloroform (10 mL) was added MCPBA (0.15 g, 0.87mmol) portionwise at 0° C. The reaction was stirred at room temperatureovernight. The mixture was partitioned between ethyl acetate and water.The combined organic layer was dried over sodium sulfate, filtered andconcentrated to give a yellow oil. This oil was dissolved in ethanol (5mL); then acetyl chloride (0.2 mL) was added dropwise at 0° C. Thereaction was stirred at this temperature for 1 h. The mixture wasconcentrated to give a crude product which was purified by preparativeHPLC to give7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(methylsulfonyl)-1H-purine-2,6(3H,7H)-dione(15 mg, 10.0% yield) as a white solid. ¹H-NMR (CD₃OD) δ 7.34-7.42 (m,4H), 5.97 (s, 2H), 4.11 (t, 2H), 3.61 (t, 2H), 3.57 (s, 3H), 3.38 (s,3H), 1.84-1.89 (m, 2H). LCMS retention time 2.052 min; LCMS MH⁺ 427

Example 717-(4-chlorobenzyl)-8-(ethylsulfonyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-8-(ethylthio)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(0.15 g, 0.29 mmol, intermediate 14) in DMF (10 mL) was addedethanethiol (27 mg, 0.44 mmol) and potassium carbonate (81 mg, 0.58mmol). The reaction was heated at 80° C. overnight. The mixture wascooled and partitioned between ethyl acetate and water. The combinedorganic layer was dried over sodium sulfate, filtered and concentratedto give a crude product which was used without purification. LCMSretention time 1.912 min; LCMS MH⁺-THP 409.

Step 27-(4-chlorobenzyl)-8-(ethylsulfonyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 70, step 2and purified by preparative HPLC to give7-(4-chlorobenzyl)-8-(ethylsulfonyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(26 mg, 20.5% yield) as a white solid. ¹H-NMR (CD₃OD) δ=7.34-7.41 (m,4H), 5.98 (s, 2H), 4.11 (t, 1H), 3.62 (t, 2H), 3.57 (s, 3H), 3.47-3.53(m, 2H), 1.85-1.90 (m, 2H), 1.31 (t, 3H). LCMS retention time 2.192 min;LCMS MH⁺ 441.

Example 727-(4-chlorobenzyl)-1-(3-hydroxypropyl)-8-(isopropylsulfonyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 71 andpurified by preparative HPLC to give7-(4-chlorobenzyl)-8-(ethylsulfonyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(26 mg, 20.5% yield) as white solid. ¹H-NMR (CDCl₃) δ 7.43-7.45 (d, 2H),7.31-7.34 (d, 2H), 5.97 (s, 2H), 4.19-4.22 (t, 2H), 3.73-3.76 (m, 1H),3.59 (s, 3H), 3.54-3.59 (m, 2H), 3.04-3.06 (t, 1H), 1.90-1.93 (m, 2H),1.38-1.40 (d, 6H). LCMS retention time 2.311 min; LCMS MH⁺ 455.

Example 737-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenylthio)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenylthio)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 71, step 1and using 3-(trifluoromethoxy)benzenethiol. Yellow oil, 100 mg, 81.9%yield. LCMS retention time 2.098 min; LCMS MH⁺-THP 541

Step 27-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenylthio)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 37, step 2.Light yellow solid, 20 mg, 23.1% yield: ¹H-NMR (DMSO-d₆) δ 7.47-7.42 (t,1H), 7.33-7.30 (m, 5H), 7.24-7.22 (d, 2H), 5.63 (s, 2H), 4.49-4.46 (t,1H), 3.95-3.92 (t, 2H), 3.47-3.42 (m, 2H), 3.39 (s, 3H), 1.72-1.69 (m,2H). LCMS retention time 2.950 min; LCMS MH⁺ 541

Example 748-(butylsulfonyl)-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 71. Lightyellow oil, 30 mg, 39.3% yield: ¹H-NMR (CD₃OD) δ 7.40-7.35 (m, 4H), 5.99(s, 2H), 4.14-4.10 (t, 2H), 3.64-3.61 (t, 2H), 3.57 (s, 3H), 3.44-3.40(m, 2H), 1.90-1.86 (m, 2H), 1.69-1.65 (m, 2H), 1.44-1.38 (m, 2H),0.92-0.89 (t, 3H). LCMS retention time 1.671 min; LCMS MH⁺ 469

Example 757-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(propylsulfonyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 71. Lightbrown solid, 30 mg, 39.5% yield: ¹H-NMR (CD₃OD) δ 7.40-7.34 (m, 4H),5.99 (s, 2H), 4.13-4.09 (t, 2H), 3.63-3.60 (t, 2H), 3.57 (s, 3H),3.43-3.39 (t, 2H), 1.89-1.85 (m, 2H), 1.80-1.75 (m, 2H), 1.04-0.99 (t,3H). LCMS retention time 2.353 min; LCMS MH⁺ 455

Example 767-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(propylsulfonyl)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)benzylthio)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-8-mercapto-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.216 mmol) in DMF (5 mL) was added1-(bromomethyl)-3-(trifluoromethoxy)benzene (66 mg, 0.259 mmol),followed by potassium carbonate (89 mg, 0.645 mmol). The reaction wasstirred at 80° C. for 2 h. The mixture was cooled, diluted with ethylacetate and water, and the phases were separated. The organic phase waswashed with brine, dried over sodium sulfate, filtered and concentratedto give7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)benzylthio)-1H-purine-2,6(3H,7H)-dione(120 mg, 87.3%) as light yellow oil. LCMS retention time 2.106 min; LCMSMH⁺-THP 555.

Step 27-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(propylsulfonyl)-1H-purine-2,6(3H,7)-dione

The title compound was prepared using the method of example 70, step 2.White solid, 14.3% yield: ¹H-NMR (CD₃OD) δ 7.47-7.43 (t, 1H), 7.32-7.30(d, 2H), 7.27-7.23 (d, 2H), 7.18-7.16 (d, 3H), 5.64 (s, 2H), 4.91 (s,2H), 4.10-4.07 (t, 2H), 3.62-3.59 (s, 5H), 1.88-1.81 (m, 2H). LCMSretention time 2.922 min; LCMS MH⁺ 587.

Example 777-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)benzylsulfinyl)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)benzylsulfinyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)benzylthio)-1H-purine-2,6(3H,7H)-dione(60 mg, 0.108 mmol, example 129, step 2) in THF (4 mL) and water (2 mL)was added Oxone (73 mg, 0.119 mmol) at 0° C. The resulting mixture wasstirred at room temperature for 16 h. The mixture was quenched withaqueous sodium thiosulfate, partitioned between DCM and water, and thephases were separated. The organic phase was washed with brine, driedover sodium sulfate, filtered and concentrated to give crude product.This crude material was purified by silica gel chromatography elutingwith petroleum/ethyl acetate (1:0 to 1:1) to give7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)benzylsulfinyl)-1H-purine-2,6(3H,7H)-dione(60 mg, 97.6%) as yellow oil. LCMS retention time 1.499 min; LCMSMH⁺-THP 571.

Step 27-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)benzylsulfinyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 37, step 2.White solid, 30 mg, 57.4% yield: ¹H-NMR (CD₃OD) δ 7.43-7.39 (t, 1H),7.27-7.23 (m, 4H), 7.17-7.12 (m, 3H), 5.59 (s, 2H), 4.89-4.74 (m, 2H),4.12-4.08 (t, 2H), 3.62-3.59 (m, 5H), 1.88-1.84 (m, 2H). LCMS retentiontime 2552 min; LCMS MH⁺ 571.

Example 787-(4-chlorobenzyl)-1-(3-hydroxypropyl)-N-isopropyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide

Step 17-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide

To a solution of7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonylchloride (115 mg, 0.295 mmol, intermediate 64) in DCM (5 mL) was addedisopropylamine (17.4 mg, 0.59 mmol) followed by TEA (60 mg, 0.59 mmol)at 0° C. and the mixture was stirred at room temperature for 1 h. Themixture was diluted with DCM and washed brine. The organic phase wasdried and concentrated to give a crude product, which was purified bysilica gel chromatography eluting with DCM/methanol (50:1) to give7-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide(59 mg, 48.6% yield) as yellow syrup. LCMS retention time 1.436 min;LCMS MH⁺ 412.

Step 27-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide

To a solution of7-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide(59 mg, 0.143 mmol) in DMF (3 mL) was added2-(3-bromopropoxy)tetrahydro-2H-pyran (32 mg, 0.143 mmol) followed bypotassium carbonate (30 mg, 0.214 mmol) and the mixture was stirred at60° C. for 4 h. The reaction was diluted with ethyl acetate and washedwith brine and saturated aqueous ammonium chloride. The organic phasewas dried and concentrated to give7-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide(61 mg, 77% yield) as yellow solid. LCMS retention time 1.805 min; LCMSMH⁺-THP 470.

Step 37-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide

A solution of7-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide(61 mg, 0.11 mmol) in 1 mM ethanolic HCl (1 mL, 1 mmol/L) was stirred atroom temperature for 30 min. The mixture was concentrated and purifiedby preparative HPLC to give7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-N-isopropyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide(17.9 mg, 34.6% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.31-7.38 (m,4H), 5.89 (s, 2H), 4.06-4.10 (t, 2H), 3.58-3.63 (m, 3H), 3.56 (s, 3H),1.83-1.87 (m, 2H), 1.19-1.21 (d, 6H). LCMS retention time 2.315 min;LCMS MH⁺ 470.

Example 797-(4-chlorobenzyl)-N-cyclopropyl-N,1-bis(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide

The title compound was prepared using the method of example 78 except instep 2, 2 equivalent of 2-(3-bromopropoxy)tetrahydro-2H-pyran was added.The final product was purified via preparative HPLC to give7-(4-chlorobenzyl)-N-cyclopropyl-N,1-bis(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide(21 mg, 38.9% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.32-7.39 (m, 4H),5.92 (s, 2H), 4.07-4.11 (t, 2H), 3.57-3.62 (m, 6H), 3.53 (s, 3H),2.71-2.75 (m, 1H), 1.84-1.95 (m, 4H), 0.91-0.94 (m, 2H), 0.75-.078 (m,2H). LCMS retention time 2.238 min; LCMS MH⁺ 526.

Example 80N-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)propane-2-sulfonamide

Step 1N-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-2,3,6,7-tetrahydro-1H-purin-8-yl)propane-2-sulfonamide

To a solution of8-amino-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(95 mg, 0.21 mmol, intermediate 53) in THF (5 mL) was added sodiumhydride (10 mg, 0.23 mmol) at 0° C. The reaction was stirred at roomtemperature for 1 h; then Isopropylsulphonyl chloride (29 mg, 0.21 mmol)was added dropwise at 0° C. The mixture was stirred at room temperature1 h. The reaction was quenched with aqueous ammonium chloride (2 mL) at0° C. and then was partitioned between ethyl acetate and water. Thecombined organic layer was dried over sodium sulfate, filtered andconcentrated to give the product as a yellow syrup(60 mg) which was usedwithout purification. LCMS retention time 1.519 min; LCMS MH⁺-THP 470.

Step 2N-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)propane-2-sulfonamide

The title compound was prepared using the method of example 37, step 2and purified by preparative HPLC. White solid, 19 mg, 37.2% yield:¹H-NMR (CD₃OD) δ 7.44 (d, 2H), 7.31-7.33 (m, 2H), 5.37 (s, 2H), 4.19 (t,2H), 3.56 (s, 2H), 3.52 (s, 3H), 3.39 (brs, 1). 3.10 (brs, 1H),1.88-1.94 (m, 2H), 1.40 (d, 6H). LCMS retention time 1.942 min; LCMS MH⁺470

Example 817-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenylamino)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenylamino)-1H-purine-2,6(3H,7H)-dione(WYS-000356-026)

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.196 mmol, Intermediate 14) in toluene(30 mL) was added3-(trifluoromethoxy) aniline (45 mg, 0.254 mmol),tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.011 mmol), X-phos (10mg, 0.021 mmol) and potassium tert-butanolate (45 mg, 0.402 mmol). Themixture was degassed and refilled with nitrogen 3 times. The reactionwas stirred at 100° C. overnight under nitrogen. The mixture wasfiltered and the filter cake was washed with ethyl acetate. The filtratewas concentrated to give a crude product which was purified by silicagel chromatography eluting with petroleum/ethyl acetate (3:1 to 3:2).The product was collected, concentrated, and dried in vacuo to give7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenylamino)-1H-purine-2,6(3H,7H)-dione(70 mg, 57.6%) as a yellow solid. LCMS MH⁺-THP 524.

Step 27-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenylamino)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared as example 36, step 2 but with aqueousethanolic HCl. White solid, 13 mg, 12.4% yield: ¹H-NMR (DMSO-d₆) δ 9.63(s, 1H), 7.91 (s, 1H), 7.63-7.61 (d, 1H), 7.45-7.38 (m, 3H), 7.24-7.22(d, 2H), 6.97-6.94 (d, 1H), 5.57 (s, 2H), 4.44-4.42 (t, 1H), 3.89-3.86(t, 2H), 3.42-3.38 (m, 4H), 3.31 (s, 3H), 1.69-1.61 (m, 2H). LCMSretention time 2.853 min; LCMS MH⁺ 524.

Example 827-(4-chlorobenzyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(80 mg, 0.17 mmol, intermediate 9) in DMF (5 mL) was added(1-(hydroxymethyl)cyclopropyl)methyl methanesulfonate (0.1 g, 0.5 mmol,intermediate 42), potassium carbonate (47 mg, 0.34 mmol) and TBAI (2 mg,0.02 mmol). The reaction was stirred at 50° C. for 8 h. The mixture wascooled and partitioned between ethyl acetate and water. The combinedorganic layer was dried over sodium sulfate, filtered and concentratedto give a crude product which was purified by preparative HPLC to give7-(4-chlorobenzyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-3-methyl-8-(3(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(36 mg, 39.9% yield) as a white solid. ¹H-NMR (CD₃OD) δ 7.39 (t, 1H),7.01 (dd, 1H), 6.88-6.90 (m, 2H), 4.87-4.88 (m, 2H), 4.44-4.46 (m, 2H),4.08-4.16 (m, 4H), 3.61 (t, 2H), 3.51 (s, 3H), 1.80-1.90 (m, 2H), 1.32(t, 3H). LCMS retention time 3.099 min; LCMS MH⁺ 533.

The following examples 83a and 83d were prepared using the method ofexample 82.

Example 83a7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopentyl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from Intermediates 9 and 43. Whitesolid, 18 mg, 17.9% yield: ¹H-NMR (CD₃OD) δ 7.54 (t, 1H), 7.44 (dd, 2H),7.32-7.36 (m, 4H), 7.22-7.25 (m, 1H), 5.48 (s, 2H), 4.14-4.18 (m, 2H),3.51 (s, 3H), 1.88-1.92 (m, 2H), 1.62-1.82 (m, 8H). LCMS retention time3.304 min; LCMS MH⁺ 561

Example 83b7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclobutyl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediates 9 and 44. Whitesolid, 20 mg, 17.9% yield: ¹H-NMR (CD₃OD) δ 7.55 (t, 1H), 7.54 (d, 2H),7.32-7.38 (m, 4H), 7.23-7.26 (m, 1H), 5.51 (s, 2H), 4.11-4.15 (m, 2H),3.50 (s, 3H), 2.05-2.17 (m, 4H), 1.93-1.97 (m, 2H), 1.76-1.80 (m, 1H)1.59-1.63 (m, 1H). LCMS retention time 3.111 min; LCMS MH⁺ 547

Example 83c7-(4-chlorobenzyl)-1-(3-hydroxy-3-methylbutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediates 9 and 45. Whitesolid, 23 mg, 39.6% yield: ¹H-NMR (CD₃OD) δ 7.55 (t, 1H), 7.44 (d, 2H),7.32-7.38 (m, 4H), 7.24 (d, 1H), 5.50 (s, 2H), 4.11-4.15 (m, 2H), 3.42(s, 3H), 1.78-1.82 (m, 2H), 1.29 (s, 6H). LCMS retention time 3.235 min;LCMS MH⁺ 535

Example 83d7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediates 9 and 46. Whitesolid, 39 mg, 33.9% yield: ¹H-NMR (CD₃OD) δ 7.55 (t, 1H), 7.44 (d, 2H),7.34-7.36 (m, 4H), 7.25 (d, 1H), 5.49 (s, 2H), 4.26 (t, 2H), 3.42 (s,3H), 1.84 (t, 2H), 0.62 (t, 2H), 0.38 (t, 2H). LCMS retention time 3.301min; LCMS MH⁺ 551

Example 847-(4-chlorobenzyl)-8-(2-(cyclohexyloxy)ethoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-8-(2-(cyclohexyloxy)ethoxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

To a solution of 2-(cyclohexyloxy)ethanol (63.4 mg, 0.439 mmol,intermediate 38) in THF (5 mL) was added sodium hydride (23.4 mg, 0.586mmol, 60% dispersion in mineral oil) at 0° C., and the mixture wasstirred at room temperature for 30 min. Then a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(150 mg, 0.293 mmol, intermediate 14) in THF (1 mL) was added and theresulting mixture was stirred at reflux for 1 h. The reaction was cooledand quenched with ice-water. The mixture was extracted with ethylacetate. The organic phase was dried and concentrated to give7-(4-chlorobenzyl)-8-(2-(cyclohexyloxy)ethoxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(123 mg, 73% yield) as a yellow solid. LCMS retention time 2.064 min;LCMS MH⁺-THP 491.

Step 27-(4-chlorobenzyl)-8-(2-(cyclohexyloxy)ethoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

A solution of7-(4-chlorobenzyl)-8-(2-(cyclohexyloxy)ethoxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(123 mg, 0.214 mmol) in 1 mM ethanolic HCl (2 mL) was stirred at roomtemperature for 30 min. The reaction was concentrated to dryness to givea crude product, which was purified by preparative HPLC to give7-(4-chlorobenzyl)-8-(2-(cyclohexyloxy)ethoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(64 mg, 60.9% yield) as a white solid. ¹H-NMR (CDCl₃) δ 7.41-7.44 (d,2H), 7.28-7.31 (d, 2H), 5.26 (s, 2H), 4.63-4.65 (m, 2H), 4.17-4.20 (t,2H), 3.81-3.84 (m, 2H), 3.68-3.70 (br, 1H), 3.21 (m, 5H), 3.30-3.34 (m,1H), 1.87-1.93 (m, 4H), 1.75-1.77 (t, 2H), 1.55-1.58 (m, 1H), 1.23-1.36(m, 5H). LCMS retention time 2.893 min; LCMS MH⁺ 491.

Example 857-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-propoxyethoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 84 andpurified by preparative HPLC to give7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-propoxyethoxy)-1H-purine-2,6(3H,7H)-dione(39 mg, 38.7% yield) as a white solid. ¹H-NMR (CD₃OD) δ 7.39-7.42 (d,2H), 7.31-7.33 (d, 2H), 5.29 (s, 2H), 4.63-4.65 (m, 2H), 4.06-4.10 (t,2H), 3.80-3.83 (m, 2H), 3.58-3.61 (t, 2H), 3.49 (s, 3H), 3.44-3.47 (t,2H), 1.84-1.87 (t, 2H), 1.55-1.60 (m, 2H), 0.90-0.94 (t, 3H). LCMSretention time 2.561 min; LCMS MH⁺ 451.

Example 867-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dionehydrochloride

The title compound was prepared from intermediate 63 using the method ofexample 55 except with 6-methylpyridin-3-ol to give 35 mg (44.1% yield)as white solid. ¹H-NMR (DMSO-d₆) δ 8.69 (s, 1H), 8.03-8.01 (d, 1H),7.59-7.57 (d, 1H), 7.45 (s, 4H), 5.45 (s, 2H), 4.06-3.98 (m, 2H),3.45-3.42 (t, 2H), 3.28 (s, 3H), 2.59 (s, 3H), 1.71-1.67 (t, 2H). LCMSretention time 2.207 min; LCMS MH⁺ 456.

Example 877-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-methylpyridin-4-yloxy)-1H-purine-2,6(3H,7H)-dionehydrochloride

The title compound was prepared using the method of example 55. Whitesolid, 30 mg, 36.6% yield: ¹H-NMR (DMSO-d₆) δ 8.48-8.46 (d, 1H), 8.17(s, 1H), 7.43-7.33 (m, 4H), 7.26-7.22 (m, 2H), 5.42 (s, 2H), 4.52 (s,1H), 3.95-3.92 (t, 2H), 3.44-3.42 (m, 2H), 3.37 (s, 3H), 2.47 (s, 3H),1.72-1.69 (t, 2H). LCMS retention time 1.716 min; LCMS MH⁺ 456.

Example 887-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(5-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 55. Whitesolid, 40 mg, 48.8% yield: ¹H-NMR (DMSO-d₆) δ 8.45-8.44 (d, 1H), 8.36(s, 1H), 7.65 (s, 1H), 7.46-7.41 (m, 4H), 5.44 (s, 2H), 4.50-4.47 (t,1H), 3.94-3.91 (t, 2H), 3.46-3.40 (m, 2H), 3.28 (s, 3H), 2.34 (s, 3H),1.73-1.66 (m, 2H). LCMS retention time 2.259 min; LCMS MH⁺ 456

Example 897-butyl-1-(3-hydroxypropyl)-3-methyl-8-(5-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7)-dione

Step 13-methyl-8-(5-methylpyridin-3-yloxy)-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 52, step 1.Yellow oil, 300 mg, 97.6% yield: LCMS retention time 1.838 min; LCMSMH⁺-THP 462

Step 27-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione

To a solution of3-methyl-8-(5-methylpyridin-3-yloxy)-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(300 mg, 0.554 mmol) in ethyl alcohol (10 ml) was added concentrated HCl(3 ml). The reaction was stirred for 6 h at 90° C. The reaction wascooled and concentrated to give7-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione(180 mg, 98.9%) as yellow oil. LCMS retention time 0.356 min; LCMS MH⁺332.

Step 37-butyl-1-(3-hydroxypropyl)-3-methyl-8-(5-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7)-dione

The title compound was prepared using the method of example 61, step 2.White solid, 30 mg, 42.8% yield: ¹H-NMR (DMSO-d₆) δ 8.48-8.47 (d, 1H),8.37-8.36 (d, 1H), 7.71 (s, 1H), 4.51-4.48 (t, 1H), 4.22-4.19 (t, 2H),3.94-3.91 (t, 2H), 3.46-3.43 (t, 2H), 3.28 (s, 3H), 2.36 (s, 3H),1.81-1.66 (m, 4H), 1.35-1.30 (m, 2H), 0.93-0.89 (t, 3H). LCMS retentiontime 1.854 min; LCMS MH⁺ 388.

Example 907-(4-chlorobenzyl)-8-(2-isopropoxyethoxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-8-(2-isopropoxyethoxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 50, step 1.Yellow oil, 100 mg, 95.2%. LCMS retention time 1.864 min; LCMS MH⁺-THP451

Step 27-(4-chlorobenzyl)-8-(2-isopropoxyethoxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 37, step 2.White solid, 30 mg, 35.1% yield: ¹H-NMR (CD₃OD) δ 7.43-7.41 (d, 2H),7.34-7.32 (d, 2H), 5.30 (s, 2H), 4.66-4.64 (m, 2H), 4.11-4.07 (t, 2H),3.83-3.81 (m, 2H), 3.68-3.58 (m, 3H), 3.50 (s, 3H), 1.88-1.85 (m, 2H),1.17-1.56 (d, 6H). LCMS retention time 2.464 min; LCMS MH⁺ 451

Example 917-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of intermediate 16,step 3. White solid, 15 mg, 21.5% yield. LCMS retention time 2.159 min;LCMS MH⁺599.

Step 27-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione(15 mg, 0.025 mmol) in DCM (1 ml) was added TFA (1 ml) dropwise followedby trifluoromethanesulfonic acid (0.25 ml), both at 0° C. The reactionwas stirred at 0° C. for 10 min, then stirred at room temperature for 16h. The reaction was quenched with aqueous saturated sodium bicarbonateand extracted with DCM. The organic phase was washed with water driedover sodium sulfate, filtered and concentrated to give7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione(10 mg, 83.7%) as yellow oil. LCMS retention time 1.821 min; LCMS MH⁺479.

Step 37-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of intermediate 14.Yellow oil, 10 mg, 76.8% yield: LCMS retention time 2.176 min; LCMSMH⁺-THP 537.

Step 47-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 37, step 2.Light yellow solid, 8 mg, 92.6% yield: ¹H-NMR (DMSO-d₆) δ 8.20-8.16 (m,2H), 7.74-7.72 (m, 2H), 7.40-7.37 (d, 2H), 7.30-7.28 (d, 2H), 5.93 (s,2H), 4.51 (s, 1H), 3.97-3.93 (t, 2H), 3.47-3.39 (m, 5H), 1.73-1.69 (m,2H). LCMS retention time 2.996 min; LCMS MH⁺ 537

Example 927-(4-chlorobenzyl)-8-(hydroxy(3-(trifluoromethoxy)phenyl)methyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione(50 mg, 0.081 mmol, example 91) in methanol (3 mL) was added sodiumborohydride (10 mg, 0.263 mmol) at 0° C. under nitrogen. The reactionwas stirred at 0° C. for 2 h. The reaction was quenched and partitionedwith ethyl acetate and water. The organic phase was washed with brine,dried over sodium sulfate, filtered and concentrated to give a crudeproduct, which was purified by preparative HPLC to give7-(4-chlorobenzyl)-8-(hydroxy(3-(trifluoromethoxy)phenyl)methyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(10 mg, 22.9%) as white solid. ¹H-NMR (CDCl₃) δ 7.36-7.31 (t, 1H),7.23-7.14 (m, 5H), 6.94-6.92 (d, 2H), 5.87-5.85 (d, 1H), 5.60-5.56 (d,1H), 5.39-5.35 (d, 1H), 4.20-4.17 (t, 2H), 3.65-3.63 (s, 4H), 3.54-3.51(m, 2H), 3.31 (s, 1H), 1.91-1.88 (t, 2H). LCMS retention time 2.605 min;LCMS MH⁺ 539.

Example 937-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-1-(4-methoxybenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione

To a solution of1-(4-methoxybenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione(130 mg, 0.261 mmol, intermediate 60) in DMF (3 mL) was added1-(bromomethyl)-4-chlorobenzene (70 mg, 0.345 mmol), followed bypotassium carbonate (107 mg, 0.775 mmol) and TBAI (5 mg, 0.014 mmol).The mixture was stirred at 60° C. overnight. The reaction was cooled andpartitioned between ethyl acetate and water. The combined organic phasewas washed with brine, dried over sodium sulfate, and concentrated togive the crude product7-(4-chlorobenzyl)-1-(4-methoxybenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione(150 mg, 92.5% yield) as a yellow oil. LCMS retention time 2.075 min;LCMS MH⁺ 629.

Step 27-(4-chlorobenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-1-(4-methoxybenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione(105 mg, 0.167 mmol) in DCM (4 mL) was added TFA (1 mL) dropwisefollowed by trifluoromethanesulfonic acid (0.25 mL) at 0° C. Thereaction was stirred at 0° C. for 10 min, then at room temperature for16 h. The reaction was quenched with saturated sodium bicarbonate andextracted with DCM. The organic phase was washed with water, dried oversodium sulfate, and concentrated to give7-(4-chlorobenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione(66 mg, 77.6% yield) as a yellow oil. LCMS retention time 2.868 min;LCMS MH⁺ 509.

Step 37-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of intermediate 14 andpurified by silica gel chromatography eluting with petroleum/ethylacetate (10:1 to 2:1) to give7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione(39 mg, 38.5% yield) as yellow oil. LCMS retention time 2.048 min; LCMSMH⁺-THP 567.

Step 47-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared as example 37, step 2 and purified viapreparative HPLC to give7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione(17 mg, 38.3% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.41-7.36 (m,3H), 7.23-7.21 (d, 2H), 6.93-6.90 (dd, 2H), 6.84 (s, 1H), 5.56 (s, 2H),4.48-4.46 (t, 1H), 4.05-4.02 (t, 2H), 3.93-3.89 (t, 2H), 3.45-3.33 (m,5H), 2.89-2.85 (t, 2H), 2.09-2.06 (t, 2H), 1.70-1.66 (t, 2H). LCMSretention time 2.925 min; LCMS MH⁺ 567.

Example 947-(4-chlorobenzyl)-8-ethyl-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of intermediate 48 andexample 91 and using propionic acid. White solid, 15 mg, 22.8% yield:¹H-NMR (CD₃OD) δ 7.35-7.33 (d, 2H), 7.20-7.18 (d, 2H), 5.58 (s, 2H),4.09-4.06 (t, 2H), 3.59-3.55 (m, 5H), 2.78-2.73 (q, 2H), 1.88-1.81 (m,2H), 1.23-1.19 (t, 3H). LCMS retention time 2.207 min; LCMS MH⁺ 377.

Example 957-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-propyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the methods of intermediate 48 andexample 91 and using butyric acid. White solid, 10 mg, 30.4% yield:¹H-NMR (CD₃OD) δ 7.33-7.31 (d, 2H), 7.20-7.17 (d, 2H), 5.58 (s, 2H),4.07-4.04 (t, 2H), 3.59-3.56 (t, 2H), 3.53 (s, 3H), 2.72-2.69 (t, 2H),1.87-1.80 (m, 2H), 1.70-1.61 (m, 2H), 0.93-0.90 (t, 3H). LCMS retentiontime 2.379 min; LCMS MH⁺ 391.

Example 967-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-(5-methylthiazol-2-yl)ethyl)-3,4,5,7-tetrahydro-1H-purine-2,6-dione

The title compound was prepared using the methods of intermediate 48 andexample 91 and using intermediate 49. White solid, 15 mg, 45.4% yield:¹H-NMR (CD₃OD) δ=7.32 (d, 2H), 7.28 (d, 1H), 7.18 (d, 1H), 5.58 (s, 2H),4.10 (t, 2H), 3.60 (t, 2H), 3.57 (s, 3H), 3.41 (t, 2H), 3.20 (t, 2H),2.40 (d, 3H), 1.85-1.89 (m, 2H). LCMS retention time 2.334 min; LCMS MH⁺474.

Example 977-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione

Step 18-bromo-7-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 7k fromintermediates 8 and 33. White solid, 275 mg, 57.5% yield. LCMS retentiontime 1.465 min; LCMS MH⁺ 441

Step 27-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 86. Whitesolid, 35 mg, 43.9% yield: ¹H-NMR (DMSO-d₆) δ 8.46-8.45 (d, 1H),7.78-7.75 (dd, 1H), 7.47-7.45 (d, 2H), 7.42-7.37 (m, 3H), 5.52 (s, 2H),4.17-4.05 (m, 2H), 3.82-3.77 (m, 1H), 3.40 (s, 3H), 2.58 (s, 3H),1.79-1.73 (m, 2H), 1.23-1.21 (d, 3H). LCMS retention time 2.390 min;LCMS MH⁺ 470

Example 981-(3-hydroxybutyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione

To a solution of3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (30m g, 0.067 mmol, intermediate 51) in DMF (3 mL) wasadded 3-hydroxybutyl-4-methylbenzenesulfonate (24.68 mg, 0.10 mmol),followed by potassium carbonate (27.93 mg, 0.20 mmol). The reaction wasstirred at 70° C. for 4 h. The mixture was partitioned between ethylacetate and water. The organic phase was washed with brine, dried oversodium sulfate, filtered and concentrated to give crude product, whichwas purified by preparative HPLC to give1-(3-hydroxybutyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione(9 mg, 25.8%) as white solid. ¹H-NMR (CD₃OD) δ 8.216 (s, 1H),7.491-7.467 (d, 1H), 7.312-7.272 (m, 1H), 7.154-6.995 (m, 4H), 5.688 (s,2H), 4.305 (s, 2H), 4.143-4.011 (m, 2H), 3.772-3.440 (m, 1H), 3.585 (s,3H), 2.283 (s, 3H), 1.761-1.703 (m, 2H), 1.194-1.179 (d, 3H). LCMSretention time 2.569 min; LCMS MH⁺ 518.

Example 991-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 98 and using1-(2-bromoethyl)cyclopropanol, intermediate 46). White solid, 8.7 mg,24.4%: ¹H-NMR (CD₃OD) δ 8.220 (s, 1H), 7.487-7.463 (d, 1H), 7.319-7.279(m, 1H), 7.169-6.984 (m, 4H), 5.690 (s, 2H), 4.315 (s, 2H), 4.256-4.221(m, 2H), 3.589 (s, 3H), 2.282 (s, 3H), 1.834-1.799 (m, 2H), 0.585-0.569(m, 2H), 0.386-0.356 (m, 2H). LCMS retention time 2.717 min; LCMS MH⁺530.

Example 1001-(3-hydroxybutyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of1-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(50 mg, 0.121 mmol, intermediate 57) in DMF (3 mL) was added2-(chloromethyl)-5-methylpyridine hydrochloride (30 mg, 0.182 mmol,intermediate 50), followed by potassium carbonate (50 mg, 0.363 mmol)and TBAI (10 mg, 0.027 mmol). The reaction was stirred at 65° C.overnight. The reaction was cooled and partitioned between ethyl acetateand water. The organic phase was washed with brine, dried over sodiumsulfate, filtered and concentrated to give a crude product, which waspurified by preparative HPLC to give1-(3-hydroxybutyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(20 mg, 31.9% yield) as white solid. ¹H-NMR (CD₃OD) δ 8.319 (s, 1H),7.663-7.640 (d, 1H), 7.553-7.510 (t, 1H), 7.348-7.316 (m, 3H),7.233-7.208 (m, 1H), 5.609 (s, 2H), 4.112-4.004 (m, 2H), 3.763-3.731 (m,1H), 3.457 (s, 3H), 2.339 (s, 3H), 1.758-1.698 (m, 2H), 1.197-1.182 (d,2H). LCMS retention time 2.714 min; LCMS MH⁺ 520.

Example 1011-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(50 mg, 0.117 mmol, intermediate 58) in DMF (3 mL) was added2-(chloromethyl)-5-methylpyridine hydrochloride (24.9 mg, 0.176 mmol,intermediate 50), followed by potassium carbonate (48.6 mg, 0.351 mmol)and TBAI (10 mg, 0.027 mmol). The reaction was stirred at 65° C.overnight. The reaction was cooled and partitioned between ethyl acetateand water. The organic phase was washed with brine, dried over sodiumsulfate, filtered and concentrated to give crude product, which waspurified by preparative HPLC to give1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(21 mg, 33.7% yield) as white solid. ¹H-NMR (CD₃OD) δ 8.320-8.315 (d,1H), 7.662-7.636 (d, 1H), 7.561-7.517 (t, 1H), 7.363-7.315 (m, 3H),7.240-7.215 (m, 1H), 5.608 (s, 2H), 4.247-4.212 (t, 2H), 3.462 (s, 3H),2.338 (s, 3H), 1.829-1.793 (t, 2H), 0.582-0.554 (m, 2H), 0.370-0.340 (m,2H). LCMS retention time 2.869 min; LCMS MH⁺ 532.

Example 1021-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 101. Whitesolid, 20 mg, 32.9% yield: ¹H-NMR (CD₃OD) δ 8.488-8.475 (d, 1H),7.831-7.627 (t, 1H), 7.562-7.521 (t, 1H), 7.446-7.427 (d, 1H),7.375-7.341 (m, 3H), 7.240-7.220 (d, 1H), 5.656 (s, 2H), 4.242-4.207 (t,2H), 3.465 (s, 3H), 1.823-1.788 (t, 2H), 0.562-0.546 (m, 2H),0.364-0.335 (m, 2H). LCMS retention time 2.759 min; LCMS MH⁺ 518.

Example 1037-((5-chloropyridin-2-yl)methyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 101. Whitesolid, 30 mg, 49.4% yield: ¹H-NMR (CD₃OD) δ 8.469-8.464 (d, 1H),7.868-7.841 (d, 1H), 7.557-7.535 (t, 1H), 7.484-7.463 (d, 1H),7.385-7.370 (m, 2H), 7.252-7.231 (d, 1H), 5.638 (s, 2H), 4.237-4.201 (t,2H), 3.460 (s, 3H), 1.820-1.784 (t, 2H), 0.563-0.548 (m, 2H),0.366-0.337 (m, 2H). LCMS retention time 3.058 min; LCMS MH⁺ 552.

Example 1047-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-((6-methylpyridin-3-yl)oxy)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(128 mg, 0.282 mmol, intermediate 56) in DMF (5 mL) was added6-methylpyridin-3-ol (37 mg, 0.338 mmol), followed by potassiumcarbonate (58 mg, 0.423 mmol). The reaction was stirred at 80° C. for 2h. The reaction was partitioned between ethyl acetate and water. Theorganic phase was washed with brine, dried over sodium sulfate, filteredand concentrated to give a crude product, which was purified bypreparative HPLC to give7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-((6-methylpyridin-3-yl)oxy)-1H-purine-2,6(3H,7H)-dione(110 mg, 80.9% yield) as white solid. ¹H-NMR (CD₃OD) δ 8.457-8.451 (d,1H), 7.776-7.748 (d, 1H), 7.470-7.374 (m, 5H), 5.519 (s, 2H),4.291-4.256 (t, 2H), 3.411 (s, 3H), 2.584 (s, 3H), 1.867-1.832 (t, 2H),0.618-0.610 (m, 2H), 0.403-0.387 (m, 2H). LCMS retention time 2.619 min;LCMS MH⁺ 482.

Example 1057-(4-chlorobenzyl)-3-methyl-1-(4,4,4-trifluorobutyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(80 mg, 0.171 mmol, intermediate 9) in DMF (2 mL) was added4,4,4-trifluorobutyl methanesulfonate (50 mg, 0.239 mmol, intermediate52), followed by potassium carbonate (71 mg, 0.518 mmol). The reactionwas stirred at 50° C. overnight. The mixture was cooled and partitionedbetween ethyl acetate and water. The organic phase was washed withbrine, dried over sodium sulfate, filtered and concentrated to give acrude product, which was purified by preparative HPLC to give1-(3-hydroxybutyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(20 mg, 31.9% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.571-7.529 (t,1H), 7.458-7.431 (m, 2H), 7.377-7.255 (m, 4H), 7.237-7.231 (m, 1H),5.496 (s, 2H), 4.098-4.063 (t, 2H), 3.423 (s, 3H), 2.288-2.219 (m, 2H),1.958-1.901 (m, 2H). LCMS retention time 3.653 min; LCMS MH⁺ 577.

Example 1067-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(propylsulfonyl)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(propylthio)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(100 mg, 0.23 mmol, example 97, step 1) in DMF (5 mL) was addedpropane-1-thiol (20.7 mg, 0.27 mmol) followed by potassium carbonate(93.9 mg, 0.68 mmol). The reaction was stirred at 60° C. for 3 h. Thereaction was partitioned between ethyl acetate and water. The organicphase was washed with brine, dried over sodium sulfate, filtered andconcentrated to give crude product (80 mg, 80.9% yield) as yellow oil.LCMS MH⁺ 437.

Step 27-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(propylsulfonyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(propylthio)-1H-purine-2,6(3H,7H)-dione(80 mg, 0.18 mmol) in CHCl₃ (10 mL) was added MCPBA (126 mg, 0.73 mmol).The reaction was stirred at room temperature overnight. The reaction wasquenched with aqueous Na₂S₂O₃ and NaHCO₃ and extracted with DCM. Thephases were separated. The organic phase was washed with aqueous NaHCO₃and brine; then it was dried over sodium sulfate, filtered andconcentrated to give a crude product, which was purified by preparativeHPLC to give7-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(propylsulfonyl)-1H-purine-2,6(3H,7H)-dione (30 mg, 34.9%) as white solid. ¹H-NMR (DMSO-d₆) δ7.429-7.408 (d, 2H), 7.278-7.257 (d, 2H), 5.870 (s, 2H), 4.511-4.500 (d,1H), 4.044-3.973 (m, 1H), 3.874-3.805 (m, 1H), 3.675-3.619 (m, 1H),3.499-3.459 (m, 2H), 3.446 (s, 3H), 1.691-1.540 (m, 4H), 1.081-1.065 (m,3H), 0.934-0.897 (m, 3H). LCMS retention time 2.599 min; LCMS MH⁺ 469.

Example 1077-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-(propylsulfonyl)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-3-methyl-8-(propylthio)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (100 mg,0.27 mmol, intermediate 8) in DMF (5 mL) was added propane-1-thiol (24.7mg, 0.32 mmol) followed by potassium carbonate (112.2 mg, 0.81 mmol).The reaction was stirred at 60° C. for 4 h. The reaction was cooled andpartitioned between ethyl acetate and water. The organic phase waswashed with brine, dried over sodium sulfate, filtered and concentratedto give a crude white solid product (124 mg, 99.9% yield). LCMS MH⁺ 365.

Step 27-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-(propylthio)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-3-methyl-8-(propylthio)-1H-purine-2,6(3H,7H)-dione(124 mg, 0.34 mmol) in DMF (7 mL) was added1-(2-bromoethyl)cyclopropanol (67.3 mg, 0.41 mmol, intermediate 46),followed by potassium carbonate (141 mg, 1.02 mmol). The reaction wasstirred at 70° C. for 5 h. The reaction was cooled and partitionedbetween ethyl acetate and water. The organic phase was washed withbrine, dried over sodium sulfate, filtered and concentrated to give acrude yellow oil product (100 mg, 66.9% yield). LCMS MH⁺ 449.

Step 37-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-(propylsulfonyl)-1H-purine-2,6(3H,7H)-dione

To a solution of7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-(propylthio)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.22 mmol) in CHCl₃ (7 mL) was added MCPBA (153 mg, 0.89 mmol)in portions. The mixture was stirred at room temperature for 3 h. Thereaction was quenched with aqueous Na₂S₂O₃ and extracted with DCM. Thephases were separated. The organic phase was washed with brine, driedover sodium sulfate, filtered and concentrated to give a crude product,which was purified by preparative HPLC to give7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-(propylsulfonyl)-1H-purine-2,6(3H,7H)-dione(20 mg, 18.7%) as white solid. ¹H-NMR (CD₃OD) δ 7.392-7.336 (m, 4H),5.982 (s, 2H), 4.285-4.248 (t, 2H), 3.567 (s, 3H), 3.445-3.406 (m, 2H),1.855-1.756 (m, 4H), 1.042-1.005 (m, 3H), 0.633-0.604 (m, 2H),0.433-0.403 (m, 2H). LCMS retention time 2.734 min; LCMS MH⁺ 481.

Example 1088-(3-chloro-5-(trifluoromethoxy)phenoxy)-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of the8-bromo-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(50 mg, 0.116 mmol, intermediate 63) in DMF (2 mL) was added3-chloro-5-(trifluoromethoxy)phenol (29.82 mg, 0.140 mmol) followed bypotassium carbonate (24.24 mg, 0.175 mmol). The reaction was stirred at85° C. for 2 h. The reaction was cooled and partitioned between ethylacetate and water. The organic phase was washed with brine, dried oversodium sulfate, filtered and concentrated to give crude product, whichwas purified by preparative HPLC to give8-(3-chloro-5-(trifluoromethoxy)phenoxy)-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(35 mg, 53.5% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.458-7.435 (m,3H), 7.381-7.365 (m, 3H), 7.361 (s, 1H), 5.507 (s, 2H), 4.138-4.102 (t,2H), 3.640-3.608 (t, 2H), 3.448 (s, 3H), 1.905-1.871 (m, 2H). LCMSretention time 3.325 min; LCMS MH⁺ 559.

Example 1097-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)phenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 108. Whitesolid, 30 mg, 47.27% yield: ¹H-NMR (CD₃OD) δ 7.588-7.566 (m, 1H),7.491-7.425 (m, 3H), 7.392-7.371 (d, 2H), 7.347-7.310 (m, 1H), 5.520 (s,2H), 4.127-4.091 (t, 2H), 3.633-3.602 (t, 2H), 3.390 (s, 3H),1.914-1.847 (m, 2H). LCMS retention time 3.099 min; LCMS MH⁺ 543.

Example 1101-(2-hydroxyethyl)-3-methyl-7-((6-methylpyridin-3-yl)methyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 42 andpurified by preparative HPLC to give1-(2-hydroxyethyl)-3,7-dimethyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione(13.1 mg, 29.9% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 8.45 (s, 2H),7.57-7.59 (d, 1H), 7.41-7.45 (t, 1H), 7.09-7.11 (d, 1H), 6.97-7.04 (m,3H), 5.20 (s, 2H), 4.79-4.81 (m, 4H), 4.73-4.75 (t, 1H), 4.41-4.43 (t,2H), 3.92-3.96 (t, 2H), 3.49-3.51 (m, 2H), 3.47 (s, 3H), 2.39 (s, 3H).LCMS retention time 2.003 min; LCMS MH⁺ 536.

Example 1117-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenyl)-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.195 mmol, intermediate 14) in toluene and ethanol (6 mL/2 mL)was added 3-(trifluoromethoxy)phenylboronic acid (60.2 mg, 0.293 mmol)followed by 1 mM aqueous sodium carbonate (1 mL). The mixture wasdegassed and refilled with a nitrogen atmosphere 3 times.Tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) was added andthe reaction was stirred at 100° C. for 16 h. The reaction was cooledand partitioned between ethyl acetate and brine The organic phase wasdried and concentrated to give a crude product (110 mg). This crudeproduct was dissolved in 1 mM ethanolic HCl (2 mL) and the mixture wasstirred at room temperature for 30 min. The mixture was concentrated andpurified by preparative HPLC to give7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenyl)-1H-purine-2,6(3H,7H)-dione(49 mg, 49.4% yield) as a white solid. ¹H-NMR (CD₃OD) δ 7.62-7.64 (t,1H), 7.55 (s, 1H), 7.51-7.53 (m, 1H), 7.29-7.31 (d, 2H), 7.22-7.24 (d,2H), 5.71 (s, 2H), 4.11-4.14 (t, 2H), 3.63 (s, 3H), 3.61-3.63 (t, 2H),1.87-1.90 (m, 2H). LCMS retention time 2.746 min; LCMS MH⁺ 509.

Example 1127-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(JF-000357-069)

The title compound was prepared from intermediate 39 using the method ofintermediate 14 to give7-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione(43.1 mg, 85.1% yield) as a yellow solid. LCMS retention time 2.046,LCMS MH⁺-THP 541.

Step 27-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the hydrolysis method of example111 to give7-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(17 mg, 38.8% yield) as a white solid. ¹H-NMR (CD₃OD) δ 7.22-7.25 (m,2H), 7.08-7.17 (m, 4H), 7.01-7.02 (d, 1H), 5.67 (s, 2H), 4.22 (s, 2H),4.08-4.11 (t, 2H), 3.59-3.62 (t, 2H), 3.54 (s, 3H), 1.85-1.89 (s, 2H).LCMS retention time 2.862 min; LCMS MH⁺ 541.

The following examples 113a to 113c were prepared using the methods ofintermediate 39 and example 112.

Example 113a8-(4-chloro-3-(trifluoromethoxy)benzyl)-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 10.7 mg, 35.2% yield: ¹H-NMR (CD₃OD) δ 7.35-7.37 (d, 1H),7.19-7.23 (m, 3H), 7.02-7.04 (m, 3H), 5.65 (s, 2H), 4.24 (s, 2H),4.09-4.12 (t, 2H), 3.58-3.62 (t, 2H), 3.59 (s, 3H), 1.86-1.89 (m, 2H).LCMS retention time 3.033 min; LCMS MH⁺ 557.

Example 113b8-(3-chloro-5-(trifluoromethoxy)benzyl)-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 24.7 mg, 35.5% yield: ¹H-NMR (CD₃OD) δ 7.19-7.21 (m, 2H),7.12 (s, 1H), 6.97-7.04 (m, 4H), 5.67 (s, 2H), 4.24 (s, 2H), 4.09-4.13(t, 2H), 3.60-3.63 (t, 2H), 3.59 (s, 3H), 1.86-1.90 (m, 2H). LCMSretention time 3.044 min; LCMS MH⁺ 557.

Example 113c7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-8-(2-methoxy-5-(trifluoromethoxy)benzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 36.5 mg, 60.1% yield: ¹H-NMR (CD₃OD) δ 7.22-7.24 (m, 2H),7.10-7.13 (d, 1H), 7.04-7.06 (d, 2H), 6.90-6.98 (m, 2H), 5.64 (s, 2H),4.15 (s, 2H), 4.07-4.11 (t, 2H), 3.78 (s, 3H), 3.58-3.61 (t, 2H), 3.55(s, 3H), 1.85-1.88 (m, 2H). LCMS retention time 2.914 min; LCMS MH⁺ 553.

Example 1141-(3-hydroxybutyl)-3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione

Step 11-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of intermediate 39 andpurified by trituration with ethanol to give1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione(136 mg, 81.6% yield) as white solid. LCMS retention time 1.638 min;LCMS MH⁺ 461.

Step 21-(4-methoxybenzyl)-3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione

To a solution of1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione(136 mg, 0.295 mmol) in DMF (2 mL) was added 2-(bromomethyl)pyridinehydrobromide (112 mg, 0.442 mmol) followed by potassium carbonate (102mg, 0.738 mmol). The reaction was stirred at 65° C. for 2 h. The mixturepartitioned between ethyl acetate and brine. The organic layer was driedand concentrated to give a crude product, which was purified by silicagel chromatography eluting with DCM/methanol (45:1) to give1-(4-methoxybenzyl)-3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione(96 mg, 59% yield) as a white solid. LCMS retention time 1.791 min; LCMSMH⁺ 552.

Step 33-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of intermediate 39,step 3 to give3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione(61 mg, 81.2% yield) as a light yellow solid. LCMS retention time 1.276min; LCMS MH⁺ 432.

Step 41-(3-hydroxybutyl)-3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione

To a solution of3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione(30 mg, 0.07 mmol) in DMF (1 mL) was added 3-hydroxybutyl4-methylbenzenesulfonate (25.6 mg, 0.105 mmol, intermediate 33) followedby potassium carbonate (14.5 mg, 0.105 mmol) and a catalytic amount ofTBAI. The reaction was stirred at 60° C. for 2 h. The reaction waspartitioned between ethyl acetate and brine. The organic phase was driedand concentrated to give crude product, which was purified bypreparative HPLC to give1-(3-hydroxybutyl)-3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione(11.2 mg, 32% yield) as white solid. ¹H-NMR (CD₃OD) δ 8.38-8.39 (d, 1H),7.65-7.69 (t, 1H), 7.23-7.31 (m, 2H), 7.07-7.17 (m, 2H), 5.72 (s, 2H),4.32 (s, 2H), 4.01-4.11 (m, 2H), 3.75-3.77 (m, 1H), 3.58 (s, 3H),1.71-1.75 (m, 2H), 1.17-1.19 (d, 3H). LCMS retention time 2.480 min;LCMS MH⁺ 504.

Example 1151-(3-hydroxybutyl)-3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 114, step 4and purified by preparative HPLC to give1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione(14.1 mg, 33.8%) as white solid. ¹H-NMR (CD₃OD) δ 8.39-8.40 (d, 1H),7.65-7.69 (t, 1H), 7.28-7.32 (t, 1H), 7.23-7.25 (m, 1H), 7.16-7.19 (d,1H), 7.08-7.12 (m, 3H), 5.72 (s, 2H), 4.33 (s, 2H), 4.21-4.24 (t, 2H),3.59 (s, 3H), 1.79-1.82 (t, 2H), 0.55-0.58 (t, 2H), 0.34-0.37 (t, 2H).LCMS retention time 2.609 min; LCMS MH⁺ 516.

Example 1167-(4-chlorobenzyl)-1-((2-hydroxycyclopentyl)methyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediates 9 and 72 using themethod of example 82 and purified by preparative HPLC to give7-(4-chlorobenzyl)-1-((2-hydroxycyclopentyl)methyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(20 mg, 33.1% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.62-7.58 (t,1H), 7.48 (s, 1H), 7.44-7.42 (m, 5H), 7.33-7.31 (dd, 1H), 5.44 (s, 2H),4.43-4.42 (d, 1H), 3.92-3.87 (m, 1H), 3.81-3.71 (m, 2H), 3.29 (s, 3H),2.21-2.16 (m, 1H), 1.85-1.19 (m, 6H). LCMS retention time 3.307 min;LCMS MH⁺ 565.

Example 1177-(4-chlorobenzyl)-1-(3-hydroxycyclobutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 11-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 52, step 1and purified by silica gel chromatography eluting with DCM/methanol(60:1) to give1-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(110 mg, 50.1% yield) as white solid. LCMS retention time 2.378 min;LCMS MH⁺ 627.

Step 27-(4-chlorobenzyl)-1-(3-hydroxycyclobutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of1-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(110 mg, 0.175 mmol) in methanol was added 5% Pd/C (15 mg). The mixturewas hydrogenated at 45 psi for 30 min. The reaction was filtered andconcentrated to give a crude product which was purified via preparativeHPLC to give7-(4-chlorobenzyl)-1-(3-hydroxycyclobutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(11 mg, 17.7% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.53-7.57 (t,1H), 7.43-7.45 (d, 2H), 7.36-7.38 (d, 2H), 7.31-7.33 (m, 1H), 7.23-7.25(d, 1H), 5.79-5.84 (m, 0.65H), 5.50 (s, 2H), 4.83-4.85 (m, 0.35H),4.64-4.66 (m, 0.65H), 4.00-4.02 (m, 0.35H), 3.40 (s, 3H), 3.16-3.19 (m,1.3H), 2.88-2.91 (m, 0.7H), 2.66-2.70 (m, 0.7H), 2.25-2.30 (m, 1.3H).LCMS retention time 3.131 min; LCMS MH⁺ 537.

Example 1187-(4-chlorobenzyl)-1-(3-hydroxycyclobutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from the product of example 117 usingthe method of example 117, step 2, but with a longer hydrogenation time.The product was purified by preparative HPLC to give7-benzyl-1-(3-hydroxycyclobutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(46 mg, 52.3% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.54-7.58 (t,1H), 7.42-7.44 (d, 2H), 7.23-7.37 (m, 5H), 7.22-7.24 (d, 1H), 5.80-5.84(m, 0.6H), 5.50 (s, 2H), 4.77-4.82 (m, 0.4H), 4.62-4.66 (m, 0.6H),4.00-4.04 (m, 0.4H), 3.39 (s, 3H), 3.16-3.23 (m, 1.2H), 2.83-2.91 (m,0.8H), 2.68-2.73 (m, 0.8H), 2.25-2.31 (m, 1.2H). LCMS retention time2.961 min; LCMS MH⁺ 503.

Example 1197-(4-chlorobenzyl)-1-(3-hydroxycyclobutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 82 withintermediates 9 and 74 and purified via preparative HPLC to give7-(4-chlorobenzyl)-1-(3-hydroxycyclopentyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(29 mg, 24.6% yield) as white solid. ¹H-NMR (DMSO-d₆) δ 7.53-7.57 (t,1H), 7.43-7.45 (d, 2H), 7.32-7.38 (m, 6H), 7.24-7.26 (dd, 1H), 5.52-5.56(m, 1H), 5.50 (s, 2H), 4.21-4.24 (m, 0.4H), 3.42 (s, 3H), 2.33-2.38 (m,1H), 2.22-2.27 (m, 1H), 2.13-2.16 (m, 1H), 1.89-1.99 (m, 2H), 1.77-1.80(m, 1H). LCMS retention time 3.168 LCMS MH⁺ 551.

Example 1207-(4-chlorobenzyl)-1-(3-(hydroxymethyl)cyclobutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 1 benzyl3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)cyclobutanecarboxylate

The title compound was prepared using the method of example 82 withintermediates 9 and 75 to give3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)cyclobutanecarboxylate(59 mg, 26.1% yield) as a yellow solid. LCMS retention time 1.981 min;LCMS MH⁺ 655.

Step 27-(4-chlorobenzyl)-1-(3-(hydroxymethyl)cyclobutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)cyclobutanecarboxylate(59 mg, 0.09 mmol) in THF (3 mL) was added LAH (6.8 mg, 0.18 mmol) inone portion and the mixture was stirred at room temperature for 2 h. Thereaction was carefully quenched with ethyl acetate and filtered. Thefiltrate was concentrated to dryness to give a crude product which waspurified via preparative HPLC to give7-(4-chlorobenzyl)-1-(3-(hydroxymethyl)cyclobutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(17 mg, 34.3% yield) as white solid. ¹H-NMR (CDCl₃) δ 7.40-7.48 (m, 3H),7.33-7.35 (m, 2H), 7.21-7.26 (m, 2H), 7.15-7.17 (d, 1H), 5.52-5.63 (m,1H), 5.44 (s, 2H), 3.73-3.80 (m, 2H), 3.11-3.17 (q, 1H), 2.96-2.98 (m,1H), 2.60-2.64 (m, 1H), 2.34-2.38 (m, 1H), 2.08-2.14 (m, 1H). LCMSretention time 3.054; LCMS MH⁺ 551.

Example 1211-(3-hydroxybutyl)-3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 57 using the method ofexample 100 and purified by preparative HPLC to give1-(3-hydroxybutyl)-3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(40 mg, 21.9% yield) as a white solid. ¹H-NMR (CD₃OD) δ 8.49-8.48 (d,1H), 7.88-7.81 (t, 1H), 7.53-7.51 (t, 1H), 7.45-7.43 (d, 1H), 7.36-7.33(m, 3H), 7.23-7.19 (d, 1H), 5.66 (s, 2H), 4.14-3.98 (m, 2H), 3.78-3.71(m, 1H), 3.46 (s, 3H), 1.75-1.71 (m, 2H), 1.19-1.18 (d, 3H). LCMSretention time 2.575 min; LCMS MH⁺ 506.

Example 1227-((5-chloropyridin-2-yl)methyl)-1-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 57 using the method ofexample 100 and purified by preparative HPLC to give7-((5-chloropyridin-2-yl)methyl)-1-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(40 mg, 21.9% yield) as a white solid. ¹H-NMR (CD₃OD) δ 8.47-8.46 (d,1H), 7.87-7.84 (d, 1H), 7.57-7.46 (t, 1H), 7.37-7.36 (d, 1H), 7.25-7.22(m, 2H), 7.14-7.12 (d, 1H), 5.64 (s, 2H), 4.13-3.97 (m, 2H), 3.78-3.72(m, 1H), 3.45 (s, 3H), 1.75-1.69 (m, 2H), 1.19-1.18 (d, 3H). LCMSretention time 2.944 min; LCMS MH⁺ 540.

Example 1237-((5-fluoropyridin-2-yl)methyl)-1-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 57 using the method ofexample 100 and purified by preparative HPLC to give7-((5-fluoropyridin-2-yl)methyl)-1-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(40 mg, 21.1% yield) as a white solid. ¹H-NMR (CD₃OD) δ 8.38-8.37 (d,1H), 7.66-7.51 (m, 3H), 7.37-7.35 (m, 2H), 7.24-7.22 (d, 1H), 5.64 (s,2H), 4.12-3.97 (m, 2H), 3.77-3.72 (m, 1H), 3.45 (s, 3H), 1.75-1.68 (m,2H), 1.19-1.18 (d, 3H). LCMS retention time 2.733 min; LCMS MH⁺ 524.

Example 1247-((5-fluoropyridin-2-yl)methyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 58 using the method ofexample 100 and purified by preparative HPLC to give7-((5-fluoropyridin-2-yl)methyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(25mg, 33.7% yield) as white solid. ¹H-NMR (CD₃OD)S 8.49 (d, 1H), 7.51-7.65(m, 3H), 7.36-7.39 (m, 2H), 7.24 (dd, 1H), 5.64 (s, 2H), 4.22 (t, 2H),3.44 (s, 3H), 1.81 (t, 2H), 0.56 (t, 2H), 0.35 (t, 2H). LCMS retentiontime 2.894 min; LCMS MH⁺ 536.

Example 1257-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-8-((5-methylpyridin-3-yl)oxy)-1H-purine-2,6(3H,7H)-dione

To a solution of8-chloro-7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione(30 mg, 0.08 mmol, intermediate 78) in DMF (2 mL) was added5-methylpyridin-3-ol (12.36 mg, 0.12 mmol), followed by potassiumcarbonate (15.66 mg, 0.11 mmol). The reaction was stirred at 80° C. for3 h. The reaction was cooled and partitioned between ethyl acetate andwater. The organic phase was washed with brine, dried over sodiumsulfate, and concentrated to give a crude product, which was purified bypreparative HPLC to give7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-8-((5-methylpyridin-3-yl)oxy)-1H-purine-2,6(3H,7H)-dione(8 mg, 22.5%) as white solid. ¹H-NMR (CD₃OD) δ 8.35-8.42 (d, 2H), 7.68(s, 1H), 7.38-7.48 (m, 4H), 5.52 (s, 2H), 4.01-4.14 (m, 4H), 3.61-3.64(m, 2H), 2.43 (s, 3H), 1.87-1.90 (m, 2H), 1.22-1.26 (m, 3H). LCMSretention time 2.511 min; LCMS MH⁺ 470.

Example 1267-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-8-(propylsulfonyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 106 andpurified by preparative HPLC to give7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-8-(propylsulfonyl)-1H-purine-2,6(3H,7H)-dione(7 mg, 16.3%) as white solid. ¹H-NMR (CD₃OD) δ 7.35-7.41 (m, 4H), 5.98(s, 2H), 4.10-4.18 (m, 4H), 3.60-3.64 (m, 2H), 3.40-3.44 (m, 2H),1.77-1.89 (m, 4H), 1.32-1.36 (m, 3H), 1.00-1.04 (m, 3H). LCMS retentiontime 2.521 min; LCMS MH⁺ 469.

Example 1278-(4-chloro-3-(trifluoromethoxy)phenoxy)-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 63 using the method ofexample 108 and purified by preparative HPLC to give8-(4-chloro-3-(trifluoromethoxy)phenoxy)-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(39.4 mg, 30.1% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.66-7.68 (d,2H), 7.58 (s, 1H), 7.44-7.46 (d, 2H), 7.36-7.40 (m, 2H), 5.51 (s, 2H),4.10-4.13 (t, 2H), 3.60-3.63 (t, 2H), 3.43 (s, 3H), 1.87-1.90 (m, 2H).LCMS retention time 3.268 min; LCMS MH⁺559.

Example 1287-(4-chlorobenzyl)-8-(4-fluoro-3-(trifluoromethoxy)phenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 63 using the method ofexample 108 and purified by preparative HPLC to give7-(4-chlorobenzyl)-8-(4-fluoro-3-(trifluoromethoxy)phenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(52.9 mg, 55.6% yield) as white solid. ¹H-NMR (CD₃OD) δ=7.55-7.56 (m,1H), 7.44-7.46 (d, 2H), 7.39-7.42 (m, 1H), 7.37-7.39 (d, 2H), 5.50 (s,2H), 4.13-4.09 (t, 2H), 3.60-3.63 (t, 2H), 3.42 (s, 3H), 1.86-1.90 (m,2H). LCMS retention time 3.114 min; LCMS MH⁺ 543.

Example 1297-(4-chlorobenzyl)-1-(3-hydroxypropyl)-8-(2-methoxy-5-(trifluoromethoxy)phenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 63 using the method ofexample 108 and purified by preparative HPLC to give7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-8-(2-methoxy-5-(trifluoromethoxy)phenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione(56.5 mg, 43.5% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.50-7.52 (d,2H), 7.38-7.40 (d, 2H), 7.37 (s, 1H), 7.21-7.26 (m, 2H), 5.49 (s, 2H),4.08-4.11 (t, 2H), 3.75 (s, 3H), 3.59-3.62 (t, 2H), 3.36 (s, 3H),1.85-1.89 (m, 2H). LCMS retention time 3.066 min; LCMS MH⁺ 555.

Example 1307-benzyl-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 80 using the methodexample 100 and purified via preparative HPLC to give7-benzyl-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-1H-purine-2,6(3H,7H)-dione(35.6 mg, 59.1% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.52-7.56 (t,1H), 7.44-7.46 (d, 2H), 7.29-7.38 (m, 5H), 7.22-7.24 (d, 1H), 5.52 (s,2H), 4.27-4.30 (t, 2H), 3.42 (s, 3H), 2.54-2.60 (m, 2H). LCMS retentiontime 3.382 min; LCMS MH⁺ 529.

Example 1317-((5-chloropyridin-2-yl)methyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 100 andpurified via preparative HPLC to give7-benzyl-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-1H-purine-2,6(3H,7H)-dione(18.7 mg, 29.1% yield) as white solid. ¹H-NMR (CD₃OD) δ 8.52 (s, 1H),8.46 (s, 1H), 7.84-7.87 (dd, 1H), 7.53-7.57 (t, 1H), 7.47-7.49 (d, 1H),7.36-7.37 (m, 1H), 7.22-7.24 (d, 1H), 5.63 (s, 2H), 4.19-4.23 (t, 2H),3.45 (s, 3H), 2.50-2.55 (m, 2H). LCMS retention time 3.369 min; LCMS MH⁺564.

Example 1327-(4-fluorobenzyl)-8-(2-fluorophenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(50 mg, 0.121 mmol, intermediate 62) in DMF (1 mL) was added2-fluorophenol (16.4 mg, 0.146 mmol) followed by potassium carbonate(25.2 mg, 0.182 mmol). The reaction was stirred at 80° C. for 4 h. Themixture was partitioned between ethyl acetate and brine. The organicphase was washed with saturated aqueous ammonium chloride, dried andconcentrated to give crude product, which was purified by preparativeHPLC to give7-(4-fluorobenzyl)-8-(2-fluorophenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(19.8 mg, 36.9% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.52-7.56 (m,2H), 7.43-7.45 (t, 1H), 7.2-7.38 (m, 3H), 7.08-7.13 (t, 1H), 5.51 (s,2H), 4.09-4.13 (t, 2H), 3.60-3.63 (t, 2H), 3.37 (s, 3H), 1.86-1.90 (m,2H). LCMS retention time 2.604; LCMS MH⁺ 443.

The compounds in Table 2 were prepared using the method of example 132.

TABLE 1 LCMS retention LCMS Example Structure Chemical Name time, minM + 1 133

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-8- phenoxy-1H-purine-2,6(3H,7H)-dione 2.576 425 134

8-(2-chlorophenoxy)-7-(4- fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 2.708 459 135

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-8-(o-tolyloxy)-1H-purine- 2,6(3H,7H)-dione 2.684 439 136

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-8-(2- methoxyphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione 2.555 455 137

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-8-(2-(trifluoromethyl)phenoxy)- 1H-purine-2,6(3H,7H)-dione 2.782 493 138

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-8- (2-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)-dione 2.828 509 139

2-((7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-8- yl)oxy)benzonitrile 2.444 450140

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-8-(2-isopropylphenoxy)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.960 467 141

8-(2-ethylphenoxy)-7-(4- fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 2.810 453 142

8-(2,3-dichlorophenoxy)-7- (4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.928 473 143

8-(3,4-difluorophenoxy)-7-(4- fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.689 461 144

8-(2,3-difluorophenoxy)-7-(4- fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.671 461 145

8-(3,5-difluorophenoxy)-7-(4- fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.727 461 146

8-(3-chlorophenoxy)-7-(4- fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 2.796 459 147

7-(4-fluorobenzyl)-8-(3- fluorophenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 2.652 443 148

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-8-(m-tolyloxy)-1H-purine- 2,6(3H,7H)-dione 2.756 439 149

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-8-(3- methoxyphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione 2.625 455 150

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)- 1H-purine-2,6(3H,7H)-dione 2.870 493 151

8-(3- (difluoromethoxy)phenoxy)- 7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.697 491 152

3-((7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-8- yl)oxy)benzonitrile 2.464 450153

8-(3-ethylphenoxy)-7-(4- fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 2.893 453 154

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-8-(3-isopropylphenoxy)-3-methyl- 1H-purine-2,6(3H,7H)-dione 3.025 467 155

8-(4-chlorophenoxy)-7-(4- fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 2.809 459 156

7-(4-fluorobenzyl)-8-(4- fluorophenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 2.619 443 157

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-8-(p-tolyloxy)-1H-purine- 2,6(3H,7H)-dione 2.766 439 158

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-8-(4- methoxyphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione 2.572 455 159

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-8-(4-(trifluoromethyl)phenoxy)- 1H-purine-2,6(3H,7H)-dione 2.889 493 160

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-8- (4-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)-dione 2.957 509 161

4-((7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-8- yl)oxy)benzonitrile 2.431 450162

8-(4-ethylphenoxy)-7-(4- fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 2.936 453 163

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-8-(4-isopropylphenoxy)-3-methyl- 1H-purine-2,6(3H,7H)-dione 3.096 467 164

7-(4-chlorobenzyl)-8-(2- chlorophenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.692 475 165

7-(4-chlorobenzyl)-1-(3- hydroxypropyl)-3-methyl-8-(o-tolyloxy)-1H-purine- 2,6(3H,7H)-dione 2.871 455 166

7-(4-chlorobenzyl)-1-(3- hydroxypropyl)-8-(2- methoxyphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.535 471 167

7-(4-chlorobenzyl)-1-(3- hydroxypropyl)-3-methyl-8-(2-(trifluoromethyl)phenoxy)- 1H-purine-2,6(3H,7H)-dione 3.695 509 168

7-(4-chlorobenzyl)-1-(3- hydroxypropyl)-3-methyl-8- (2-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)-dione 3.003 525 169

2-((7-(4-chlorobenzyl)-1-(3- hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-8- yl)oxy)benzonitrile 2.601 466170

7-(4-chlorobenzyl)-1-(3- hydroxypropyl)-8-(2-isopropylphenoxy)-3-methyl- 1H-purine-2,6(3H,7H)-dione 3.100 483 171

7-(4-chlorobenzyl)-8-(2- ethylphenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.035 469 172

7-(4-chlorobenzyl)-8-(2,3- dichlorophenoxy)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 3.086 510 173

7-(4-chlorobenzyl)-8-(3,4- difluorophenoxy)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 3.636 477 174

7-(4-chlorobenzyl)-8-(2,3- difluorophenoxy)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 3.640 477 175

7-(4-chlorobenzyl)-8-(3,5- difluorophenoxy)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 3.673 477 176

7-(4-chlorobenzyl)-8-(3- ethylphenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.822 469 177

7-(4-chlorobenzyl)-1-(3- hydroxypropyl)-8-(3-isopropylphenoxy)-3-methyl- 1H-purine-2,6(3H,7H)-dione 3.218 483 178

7-(4-chlorobenzyl)-8-(4- fluorophenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.569 459 179

7-(4-chlorobenzyl)-1-(3- hydroxypropyl)-8-(4- methoxyphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.587 471 180

7-(4-chlorobenzyl)-1-(3- hydroxypropyl)-3-methyl-8-(4-(trifluoromethyl)phenoxy)- 1H-purine-2,6(3H,7H)-dione 3.044 509 181

7-(4-chlorobenzyl)-1-(3- hydroxypropyl)-3-methyl-8- (4-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)-dione 3.099 525 182

4-((7-(4-chlorobenzyl)-1-(3- hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-8- yl)oxy)benzonitrile 3.327 466183

7-(4-chlorobenzyl)-8-(4- ethylphenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.098 469 184

7-(4-chlorobenzyl)-1-(3- hydroxypropyl)-8-(4-isopropylphenoxy)-3-methyl- 1H-purine-2,6(3H,7H)-dione 3.239 483 185

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8-phenoxy-1H-purine- 2,6(3H,7H)-dione 2.418 442 186

8-(2-chlorophenoxy)-7-((5- chloropyridin-2-yl)methyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.548 476 187

7-((5-chloropyridin-2- yl)methyl)-8-(2- fluorophenoxy)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.409 460 188

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8-(o-tolyloxy)-1H-purine- 2,6(3H,7H)-dione 2.566 456 189

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-8-(2-methoxyphenoxy)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.346 472 190

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8-(2-(trifluoromethyl)phenoxy)- 1H-purine-2,6(3H,7H)-dione 1.586 510 191

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8- (2-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)-dione 1.611 526 192

2-((7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-8- yl)oxy)benzonitrile 2.273 467193

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-8-(2-isopropylphenoxy)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.810 484 194

7-((5-chloropyridin-2- yl)methyl)-8-(2- ethylphenoxy)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.682 470 195

7-((5-chloropyridin-2- yl)methyl)-8-(2,3- dichlorophenoxy)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.760 510 196

7-((5-chloropyridin-2- yl)methyl)-8-(3,4- difluorophenoxy)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 1.535 478 197

7-((5-chloropyridin-2- yl)methyl)-8-(2,3- difluorophenoxy)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 1.507 478 198

7-((5-chloropyridin-2- yl)methyl)-8-(3,5- difluorophenoxy)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 1.560 478 199

8-(3-chlorophenoxy)-7-((5- chloropyridin-2-yl)methyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.648 476 200

7-((5-chloropyridin-2- yl)methyl)-8-(3- fluorophenoxy)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.476 460 201

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8-(m-tolyloxy)-1H-purine- 2,6(3H,7H)-dione 2.584 456 202

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-8-(3-methoxyphenoxy)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.432 472 203

7-((5-chloropyridin-2- yl)methyl)-1-(3-hydroxy- propylmethyl)phenoxy)-1H-purine-2,6(3H,7H)- dione 2.735 510 204

7-((5-chloropyridin-2- yl)methyl)-8-(3- (difluoromethoxy)phenoxy)-1-(3-hydroxypropyl)-3- methyl-1H-purine- 2,6(3H,7H)-dione 1.528 508 205

3-((7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-8- yl)oxy)benzonitrile 2.296 467206

7-((5-chloropyridin-2- yl)methyl)-8-(3- ethylphenoxy)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.748 470 207

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-8-(3-isopropylphenoxy)-3-methyl- 1H-purine-2,6(3H,7H)-dione 1.753 484 208

8-(4-chlorophenoxy)-7-((5- chloropyridin-2-yl)methyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.676 476 209

7-((5-chloropyridin-2- yl)methyl)-8-(4- fluorophenoxy)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.477 460 210

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8-(p-tolyloxy)-1H-purine- 2,6(3H,7H)-dione 2.598 456 211

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-8-(4-methoxyphenoxy)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.433 472 212

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8-(4-(trifluoromethyl)phenoxy)- 1H-purine-2,6(3H,7H)-dione 2.746 510 213

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8- (4-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)-dione 2.802 526 214

4-((7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-8- yl)oxy)benzonitrile 2.270 467215

7-((5-chloropyridin-2- yl)methyl)-8-(4- ethylphenoxy)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)-dione 1.667 470 216

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-8-(4-isopropylphenoxy)-3-methyl- 1H-purine-2,6(3H,7H)-dione 2.944 484 217

7-benzyl-8-(2- chlorophenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 2.672 441 218

7-benzyl-8-(2- fluorophenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.381 425 219

7-benzyl-1-(3- hydroxypropyl)-3-methyl-8- (o-tolyloxy)-1H-purine-2,6(3H,7H)-dione 2.664 421 220

7-benzyl-1-(3- hydroxypropyl)-8-(2- methoxyphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.349 437 221

7-benzyl-1-(3- hydroxypropyl)-3-methyl-8- (2-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione 3.519 475 222

7-benzyl-1-(3- hydroxypropyl)-3-methyl-8- (2-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)-dione 2.801 491 223

2-((7-benzyl-1-(3- hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-8- yl)oxy)benzonitrile 3.122 432224

7-benzyl-1-(3- hydroxypropyl)-8-(2- isopropylphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.685 449 225

7-benzyl-8-(2-ethylphenoxy)- 1-(3-hydroxypropyl)-3- methyl-1H-purine-2,6(3H,7H)-dione 2.807 435 226

7-benzyl-8-(2,3- dichlorophenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 2.884 475 227

7-benzyl-8-(3,4- difluorophenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.451 443 228

7-benzyl-8-(2,3- difluorophenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.449 443 229

7-benzyl-8-(3,5- difluorophenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.505 443 230

7-benzyl-1-(3- hydroxypropyl)-3-methyl-8- (m-tolyloxy)-1H-purine-2,6(3H,7H)-dione 3.541 421 231

7-benzyl-1-(3- hydroxypropyl)-8-(3- methoxyphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.399 437 232

7-benzyl-1-(3- hydroxypropyl)-3-methyl-8- (3-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)-dione 2.603 491 233

3-((7-benzyl-1-(3- hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-8- yl)oxy)benzonitrile 3.160 432234

7-benzyl-8-(3-ethylphenoxy)- 1-(3-hydroxypropyl)-3- methyl-1H-purine-2,6(3H,7H)-dione 3.669 435 235

7-benzyl-1-(3- hydroxypropyl)-8-(3- isopropylphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.015 449 236

4-((7-benzyl-1-(3- hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-8- yl)oxy)benzonitrile 3.140 432237

7-benzyl-8-(4- chlorophenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.578 441 238

7-benzyl-8-(4- fluorophenoxy)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.392 425 239

7-benzyl-1-(3- hydroxypropyl)-3-methyl-8- (p-tolyloxy)-1H-purine-2,6(3H,7H)-dione 3.558 421 240

7-benzyl-1-(3- hydroxypropyl)-8-(4- methoxyphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.389 437 241

7-benzyl-1-(3- hydroxypropyl)-3-methyl-8- (4-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)-dione 3.640 491 242

7-benzyl-1-(3- hydroxypropyl)-3-methyl-8- (4-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione 3.588 475 243

7-benzyl-8-(4-ethylphenoxy)- 1-(3-hydroxypropyl)-3- methyl-1H-purine-2,6(3H,7H)-dione 2.912 435 244

7-benzyl-1-(3- hydroxypropyl)-8-(4- isopropylphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione 3.054 449 245

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8- phenoxy-1H-purine-2,6(3H,7H)-dione 2.936 455 246

7-(4-chlorobenzyl)-8-(2- chlorophenoxy)-3-ethyl-1-(3-hydroxypropyl)-1H-purine- 2,6(3H,7H)-dione 3.034 489 247

7-(4-chlorobenzyl)-3-ethyl-8- (2-fluorophenoxy)-1-(3-hydroxypropyl)-1H-purine- 2,6(3H,7H)-dione 2.835 473 248

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8-(o-tolyloxy)-1H-purine- 2,6(3H,7H)-dione 2.021 469 249

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8-(2-methoxyphenoxy)-1H-purine- 2,6(3H,7H)-dione 2.884 485 250

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8-(2-(trifluoromethyl)phenoxy)- 1H-purine-2,6(3H,7H)-dione 3.063 523 251

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8-(2-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)-dione 3.120 539 252

2-((7-(4-chlorobenzyl)-3- ethyl-1-(3-hydroxypropyl)-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-8- yl)oxy)benzonitrile 3.673 480253

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8-(2-isopropylphenoxy)-1H- purine-2,6(3H,7H)-dione 3.252 497 254

7-(4-chlorobenzyl)-3-ethyl-8- (2-ethylphenoxy)-1-(3-hydroxypropyl)-1H-purine- 2,6(3H,7H)-dione 3.144 483 255

7-(4-chlorobenzyl)-8-(2,3- dichlorophenoxy)-3-ethyl-1-(3-hydroxypropyl)-1H- purine-2,6(3H,7H)-dione 3.249 525 256

7-(4-chlorobenzyl)-8-(3,4- difluorophenoxy)-3-ethyl-1-(3-hydroxypropyl)-1H- purine-2,6(3H,7H)-dione 3.047 491 257

7-(4-chlorobenzyl)-8-(2,3- difluorophenoxy)-3-ethyl-1-(3-hydroxypropyl)-1H- purine-2,6(3H,7H)-dione 2.898 491 258

7-(4-chlorobenzyl)-8-(3,5- difluorophenoxy)-3-ethyl-1-(3-hydroxypropyl)-1H- purine-2,6(3H,7H)-dione 3.051 491 259

7-(4-chlorobenzyl)-8-(3- chlorophenoxy)-3-ethyl-1-(3-hydroxypropyl)-1H-purine- 2,6(3H,7H)-dione 3.148 489 260

7-(4-chlorobenzyl)-3-ethyl-8- (3-fluorophenoxy)-1-(3-hydroxypropyl)-1H-purine- 2,6(3H,7H)-dione 3.901 473 261

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8-(m-tolyloxy)-1H-purine- 2,6(3H,7H)-dione 3.001 469 262

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8-(3-methoxyphenoxy)-1H-purine- 2,6(3H,7H)-dione 2.904 485 263

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8-(3-(trifluoromethyl)phenoxy)- 1H-purine-2,6(3H,7H)-dione 3.138 523 264

7-(4-chlorobenzyl)-8-(3- (difluoromethoxy)phenoxy)-3-ethyl-1-(3-hydroxypropyl)- 1H-purine-2,6(3H,7H)-dione 2.976 521 265

3-((7-(4-chlorobenzyl)-3- ethyl-1-(3-hydroxypropyl)-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-8- yl)oxy)benzonitrile 2.690 480266

7-(4-chlorobenzyl)-3-ethyl-8- (3-ethylphenoxy)-1-(3-hydroxypropyl)-1H-purine- 2,6(3H,7H)-dione 2.221 483 267

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8-(3-isopropylphenoxy)-1H- purine-2,6(3H,7H)-dione 3.361 497 268

7-(4-chlorobenzyl)-8-(4- chlorophenoxy)-3-ethyl-1-(3-hydroxypropyl)-1H-purine- 2,6(3H,7H)-dione 3.153 489 269

7-(4-chlorobenzyl)-3-ethyl-8- (4-fluorophenoxy)-1-(3-hydroxypropyl)-1H-purine- 2,6(3H,7H)-dione 2.952 473 270

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8-(p-tolyloxy)-1H-purine- 2,6(3H,7H)-dione 3.082 469 271

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8-(4-methoxyphenoxy)-1H-purine- 2,6(3H,7H)-dione 2.907 485 272

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8-(4-(trifluoromethyl)phenoxy)- 1H-purine-2,6(3H,7H)-dione 3.193 523 273

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8-(4-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)-dione 3.169 539 274

4-((7-(4-chlorobenzyl)-3- ethyl-1-(3-hydroxypropyl)-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-8- yl)oxy)benzonitrile 2.713 480275

7-(4-chlorobenzyl)-3-ethyl-8- (4-ethylphenoxy)-1-(3-hydroxypropyl)-1H-purine- 2,6(3H,7H)-dione 3.267 483 276

7-(4-chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-8-(4-isopropylphenoxy)-1H- purine-2,6(3H,7H)-dione 3.408 497

Example 2777-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-p-tolyl-1H-purine-2,6(3H,7H)-dione

To a solution of8-bromo-7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(50 mg, 0.121 mmol, intermediate 62) in toluene (2 mL) and ethanol (0.5mL) was added p-tolylboronic acid (19.7 mg, 0.145 mmol) followed byaqueous sodium carbonate solution (0.5 mL), and the mixture was degassedunder nitrogen atmosphere three times.Tetrakis(triphenylphosphine)platinum (7.5 mg, 0.006 mmol) was added tothe reaction under nitrogen and the resulting mixture was stirred at100° C. for 16 h. The mixture was partitioned between ethyl acetate andbrine. The organic phase was dried and concentrated to give crudeproduct, which was purified via preparative HPLC to give7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-p-tolyl-1H-purine-2,6(3H,7H)-dione(20.9 mg, 40.9% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.51-7.53 (d,2H), 7.34-7.36 (d, 2H), 6.97-7.07 (m, 4H), 5.66 (s, 2H), 4.09-4.12 (t,2H), 3.59-3.62 (t, 2H), 3.59 (s, 3H), 2.44 (s, 3H), 1.85-1.89 (m, 2H).LCMS retention time 2.306; LCMS MH⁺ 423.

The examples in Table 3 were prepared using the method of example 277.

TABLE 2 LCMS retention LCMS Example Structure Chemical Name time, minM + 1 278

8-(3-chlorophenyl)-7-(4- fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)- dione 2.644 443 279

7-(4-fluorobenzyl)-8-(3- fluorophenyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)- dione 2.425 427 280

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl- 8-m-tolyl-1H-purine-2,6(3H,7H)-dione 2.577 423 281

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-8-(3- methoxyphenyl)-3-methyl-1H-purine-2,6(3H,7H)- dione 2.388 439 282

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-8-(3- isopropylphenyl)-3-methyl-1H-purine- 2,6(3H,7H)-dione 2.868 451 283

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl- 8-(3-(trifluoromethyl)phenyl)- 1H-purine-2,6(3H,7H)- dione 2.664 477 284

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl- 8-(3-(trifluoromethoxy)phenyl)- 1H-purine-2,6(3H,7H)- dione 2.782 493 285

8-(biphenyl-3-yl)-7-(4- fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)- dione 2.572 485 286

8-(4-chlorophenyl)-7-(4- fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)- dione 2.613 443 287

7-(4-fluorobenzyl)-8-(4- fluorophenyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)- dione 2.401 427 288

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-8-(4- methoxyphenyl)-3-methyl-1H-purine-2,6(3H,7H)- dione 2.367 439 289

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl- 8-(4-(trifluoromethyl)phenyl)- 1H-purine-2,6(3H,7H)- dione 2.453 477 290

8-(2-chlorophenyl)-7-(4- fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)- dione 2.219 443 291

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl- 8-(o-tolyl)-1H-purine-2,6(3H,7H)-dione 2.432 423 292

7-(4-fluorobenzyl)-8-(2- fluorophenyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)- dione 2.307 427 293

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-8-(2- methoxyphenyl)-3-methyl-1H-purine-2,6(3H,7H)- dione 2.303 439 294

2-(7-(4-fluorobenzyl)-1- (3-hydroxypropyl)-3- methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8- yl)benzonitrile 2.204 434 295

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-8-(2- isopropylphenyl)-3-methyl-1H-purine- 2,6(3H,7H)-dione 2.507 451 296

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl- 8-(2-(trifluoromethyl)phenyl)- 1H-purine-2,6(3H,7H)- dione 2.461 477 297

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl- 8-(2-(trifluoromethoxy)phenyl)- 1H-purine-2,6(3H,7H)- dione 2.341 493 298

8-(2-ethylphenyl)-7-(4- fluorobenzyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)- dione 2.602 437 299

8-(3-chlorophenyl)-7-((5- chloropyridin-2- yl)methyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)- dione 2.533 461 300

7-((5-chloropyridin-2- yl)methyl)-8-(3- fluorophenyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)- dione 2.313 444 301

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8-(m-tolyl)-1H-purine- 2,6(3H,7H)-dione 2.432 440 302

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-8-(3-methoxyphenyl)-3-methyl- 1H-purine-2,6(3H,7H)- dione 2.276 456 303

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-8-(3-isopropylphenyl)-3- methyl-1H-purine- 2,6(3H,7H)-dione 2.791 468 304

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl- 8-(3-(trifluoromethyl)phenyl)- 1H-purine-2,6(3H,7H)- dione 2.614 494 305

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl- 8-(3-(trifluoromethoxy)phenyl)- 1H-purine-2,6(3H,7H)- dione 2.735 510 306

8-([1,1′-biphenyl]-3-yl)-7- ((5-chloropyridin-2- yl)methyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)- dione 2.750 502 307

8-(4-chlorophenyl)-7-((5- chloropyridin-2- yl)methyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)- dione 2.501 461 308

7-((5-chloropyridin-2- yl)methyl)-8-(4- fluorophenyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)- dione 2.281 444 309

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8-(p-tolyl)-1H-purine- 2,6(3H,7H)-dione 2.413 440 310

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-8-(4-methoxyphenyl)-3-methyl- 1H-purine-2,6(3H,7H)- dione 2.360 456 311

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl- 8-(4-(trifluoromethyl)phenyl)- 1H-purine-2,6(3H,7H)- dione 2.666 494 312

8-(2-chlorophenyl)-7-((5- chloropyridin-2- yl)methyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)- dione 2.100 461 313

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8-(o-tolyl)-1H-purine- 2,6(3H,7H)-dione 2.306 440 314

7-((5-chloropyridin-2- yl)methyl)-8-(2- fluorophenyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)- dione 2.175 444 315

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-8-(2-methoxyphenyl)-3-methyl- 1H-purine-2,6(3H,7H)- dione 2.252 456 316

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-8-(2-isopropylphenyl)-3- methyl-1H-purine- 2,6(3H,7H)-dione 2.668 468 317

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl- 8-(2-(trifluoromethoxy)phenyl)- 1H-purine-2,6(3H,7H)- dione 2.464 510 318

7-((5-chloropyridin-2- yl)methyl)-8-(2- ethylphenyl)-1-(3-hydroxypropyl)-3-methyl- 1H-purine-2,6(3H,7H)- dione 2.577 454

Example 3197-((5-fluoropyridin-3-yl)methyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

To a solution of1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(60 mg, 0.15 mmol, intermediate 15) in DMF (5 mL) was added3-(chloromethyl)-5-fluoropyridine (80 mg, 0.55 mmol), potassiumcarbonate (0.55 g, 0.6 mmol), and TBAI (2 mg, 0.02 mmol). The reactionwas heated at 60° C. for 2 h. The mixture was cooled and partitionedbetween ethyl acetate and water. The organic phase was dried over sodiumsulfate, and concentrated. The residue was purified by preparative HPLCto give7-((5-fluoropyridin-3-yl)methyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(35mg, 46% yield) as white solid. LCMS retention time 2.577 min; LCMS MH⁺510.

Example 3201-(3-hydroxypropyl)-3-methyl-7-((6-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 319 andpurified via preparative HPLC to give1-(3-hydroxypropyl)-3-methyl-7-((6-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(20 mg, 36.2% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.60-7.56 (t, 1H),7.42-7.40 (m, 2H), 7.27-7.25 (d, 1H), 4.30-4.26 (t, 2H), 4.13-4.10 (t,2H), 3.64-3.61 (t, 2H), 3.44 (s, 3H), 1.94-1.87 (m, 4H), 1.02-0.980 (t,3H). LCMS retention time 2.803 min; LCMS MH⁺ 443.

The examples in Table 3 were prepared using the methods of example 319.

TABLE 3 LCMS retention LCMS Example Structure Chemical Name time, minM + 1 321

1-(3-hydroxypropyl)-3- methyl-7-((6-methylpyridin- 2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)- dione 2.525 506 322

7-((4-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8- (3-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)- dione 2.785 526 323

1-(3-hydroxypropyl)-3- methyl-8-(3- (trifluoromethoxy)phenoxy)- 7-((6-(trifluoromethyl)pyridin-3- yl)methyl)-1H-purine- 2,6(3H,7H)-dione 2.845560 324

1-(3-hydroxypropyl)-3- methyl-7-((6-methylpyridin- 3-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)- dione 2.525 506 325

1-(3-hydroxypropyl)-7-((6- methoxypyridin-3- yl)methyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)- dione 2.775 522 326

7-((5-chloropyridin-3- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8- (3-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)- dione 2.715 526 327

l-(3-hydroxypropyl)-3- methyl-7-((5-methylpyridin- 3-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)- dione 2.234 506 328

7-((3-chloropyridin-4- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8- (3-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)- dione 2.692 526 329

7-((3-fluoropyridin-4- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8- (3-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)- dione 2.568 510 330

1-(3-hydroxypropyl)-3- methyl-8-(3- (trifluoromethoxy)phenoxy)-7-(3,3,3-trifluoropropyl)- 1H-purine-2,6(3H,7H)- dione 2.803 497 331

1-(3-hydroxypropyl)-7-(3- methoxypropyl)-3-methyl- 8-(3-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)- dione 2.627 473 332

1-(3-hydroxypropyl)-7-(2- methoxyethyl)-3-methyl-8- (3-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)- dione 2.632 459 333

1-(3-hydroxypropyl)-7- isopentyl-3-methyl-8-(3-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)- dione 1.861 471 334

7-((4-chloropyridin-3- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8- (3-(trifluoromethoxy)phenoxy)- 1H-purine-2,6(3H,7H)- dione 2.744 522

Example 3357-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-8-propoxy-1H-purine-2,6(3H,7H)-dione

To a solution of8-chloro-3-ethyl-7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione(50 mg, 0.117 mmol, intermediate 78) in propanol (5 mL) was added sodium(10 mg, 0.43 mmol). The reaction was stirred at room temperature for 1h. The reaction was partitioned between ethyl acetate and brine. Theorganic phase was dried and concentrated to give a crude product, whichwas purified via preparative HPLC to give7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-8-propoxy-1H-purine-2,6(3H,7H)-dione(11.6 mg, 24.4% yield) as white solid. ¹H-NMR (CD₃OD) δ 7.24-7.29 (s,4H), 5.21 (s, 2H), 4.39-4.42 (t, 2H), 3.98-4.05 (m, 4H), 3.49-3.53 (m,2H), 1.73-1.81 (m, 4H), 1.20-1.23 (m, 3H), 0.90-0.94 (m, 3H). LCMSretention time 2.881; LCMS MH⁺ 421.

The examples in Table 4 were prepared using the method of example 335.

TABLE 4 LCMS LCMS Example Structure Chemical Name retention time M + 1336

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-8- methoxy-3-methyl-1H-purine-2,6(3H,7H)-dione 2.156 363 337

8-ethoxy-7-(4- fluorobenzyl)-1-(3- hydroxypropyl)-3- methyl-1H-purine-2,6(3H,7H)-dione 2.366 377 338

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-3- methyl-8-propoxy-1H-purine-2,6(3H,7H)-dione 2.528 391 339

7-(4-fluorobenzyl)-1-(3- hydroxypropyl)-8- isopropoxy-3-methyl-1H-purine-2,6(3H,7H)- dione 2.570 391 340

8-butoxy-7-(4- fluorobenzyl)-1-(3- hydroxypropyl)-3- methyl-1H-purine-2,6(3H,7H)-dione 2.804 405 341

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-8-methoxy-3-methyl-1H- purine-2,6(3H,7H)-dione 1.937 380 342

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-8-propoxy-1H- purine-2,6(3H,7H)-dione 2.319 408 343

7-((5-chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-8-isopropoxy-3-methyl- 1H-purine-2,6(3H,7H)- dione 2.357 408 344

8-butoxy-7-((5- chloropyridin-2- yl)methyl)-1-(3- hydroxypropyl)-3-methyl-1H-purine- 2,6(3H,7H)-dione 2.588 422 345

7-(4-chlorobenzyl)-3- ethyl-1-(3- hydroxypropyl)-8- methoxy-1H-purine-2,6(3H,7H)-dione 2.537 393 346

7-(4-chlorobenzyl)-3- ethyl-1-(3- hydroxypropyl)-8-isopropoxy-1H-purine- 2,6(3H,7H)-dione 2.932 421 347

8-butoxy-7-(4- chlorobenzyl)-3-ethyl-1- (3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione 3.171 435

Example 3487-(4-Chlorobenzyl)-3-methyl-1-(2-oxopropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

7-(4-Chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.25 g, 0.54 mmol, intermediate 9), potassium carbonate (0.11 g, 0.80mmol), TBAI (0.10 g) and 1-chloropropan-2-one (0.040 mL, 0.59 mmol) werecombined in DMF (3 mL) and heated at 50° C. for 1.5 h. The reaction wascooled to room temperature, diluted with water (100 mL) and extractedwith ethyl acetate (3×75 mL). The combined organic extracts were washedwith 1N lithium chloride (2×75 mL) dried with magnesium sulfate,filtered and evaporated under reduced pressure to an off-white solid.The solid was purified using a 25 g silica gel flash column eluted with1% methanol/DCM to give7-(4-chlorobenzyl)-3-methyl-1-(2-oxopropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.22 g, 79% yield) as a white solid. LCMS retention time 4.433 minutesand 99% purity, LCMS MH⁺ 523. ¹H NMR (DMSO-d₆) δ 7.60 (t, 1H, J=8 Hz),7.50-7.53 (m, 1H), 7.38-7.47 (m, 5H), 7.32 (d, 1H, J=8 Hz), 5.40 (s,2H), 4.73 (s, 2H) 3.28 (s, 3H), 2.19 (s, 3H).

Example 3497-(4-Chlorobenzyl)-3-methyl-1-((3-methylisoxazol-5-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 348. Whitesolid. LCMS retention time=4.601 minutes and 99% purity, LCMS MH⁺ 562.¹H NMR (DMSO-d₆) δ (DMSO-d₆) δ 7.60 (t, 1H, J=8 Hz), 7.47-7.51 (m, 1H),7.40-7.45 (m, 5H), 7.32 (d, 1H, J=8 Hz), 6.20 (s, 1H), 5.43 (s, 2H),5.13 (s, 2H), 3.30 (s, 3H), 2.17 (s, 3H).

Example 350Ethyl-2(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate

The title compound was prepared using the method of example 348. Whitesolid. LCMS retention time=4.697 minutes and 99% purity, LCMS MH⁺ 553.¹H NMR (DMSO-d₆) δ 7.58 (t, 1H, J=8 Hz), 7.51-7.54 (m, 1H), 7.38-7.47(m, 5H), 7.32 (d, 1H, J=12 Hz), 5.41 (s, 2H), 4.60 (s, 2H), 4.12 (dd,2H, J=8 Hz and 16 Hz), 3.30 (s, 3H). 1.18 (t, 3H, J=8 Hz).

Example 3517-(4-Chlorobenzyl)-1-(2-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

7-(4-Chlorobenzyl)-3-methyl-1-(2-oxopropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.18 g, 0.35 mmol, example 348) was dissolved in methanol (3 mL) andcooled to 0° C. Then sodium borohydride (0.040 g, 1.05 mmol) was addedportion wise over 20 minutes. The reaction was stirred in the cold for 2h. The reaction solvent was removed under reduced pressure, then dilutedwith water (100 mL) and extracted with ethyl acetate (3×75 mL). Thecombined extracts were dried with magnesium sulfate, filtered andevaporated under reduced pressure to a light golden solid. Solid waspurified using a 12 g silica gel flash column eluted with 1%methanol/DCM to give7-(4-chlorobenzyl)-1-(2-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.15 g, 79% yield) as a white solid. LCMS retention time=4.280 minutesand 97% purity, LCMS MH⁺ 525. ¹H NMR (DMSO-d₆) δ 7.59 (t, 1H, J=8 Hz),7.46-7.48 (m, 1H), 7.38-7.43 (m, 5H), 7.31 (d, 1H, J=8 Hz), 5.43 (s,2H), 4.65 (d, 1H, J=8 Hz), 3.90-3.95 (m, 2H), 3.68-3.74 (m, 1H), 3.28(s, 3H), 1.02 (d, 3H, J=8 Hz).

Example 352(S*)-1-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propan-2ylacetate

and(R*)-7-(4-chlorobenzyl)-1-(2-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-2,6(3H,7H)-dione

7-(4-Chlorobenzyl)-1-(2-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.25 g, 0.48 mmol, example 351), vinyl acetate (0.15 mL, 1.67 mmol) andcandida antartica acrylic resin (“Novozym”) (0.14 g) were combined inethyl acetate (5 mL) and stirred at room temperature for 24 h. Thereaction was filtered and the filtrate was evaporated under reducedpressure to a clear oil. The oil was purified using a 25 g silica gelflash column eluted with a gradient of 20% to 30% ethyl acetate/hexanesto yield both(S*)-1-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propan-2ylacetate (0.12 g, 91% yield). LCMS retention time=4.448 minutes and 94%purity, LCMS MH⁺ 567. ¹H NMR (DMSO-d₆) δ 7.60 (t, 1H, J=8 Hz), 7.48-7.54(m, 1H), 7.38-7.45 (m, 5H), 7.32 (d, 1H, J=8 Hz), 5.42 (s, 2H),5.10-5.19 (m, 1H), 4.13-4.22 (m, 1H), 3.85 (dd, 1H, J=4 Hz and 12 Hz),3.27 (s, 3H), 1.79 (s, 3H), 1.17 (d, 3H, J=4 Hz) and(R*)-7-(4-chlorobenzyl)-1-(2-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-2,6(3H,7H)-dione(0.11 g, 88% yield) as a clear oil. LCMS retention time=4.019 minutesand 95% purity, LCMS MH⁺=525. ¹H NMR (DMSO-d₆) δ 7.59 (t, 1H, J=8 Hz),7.45-7.48 (m, 1H), 7.39-7.44 (m, 5H), 7.31 (d, 1H, J=8 Hz), 5.43 (s,2H), 4.65 (d, 1H, J=4 Hz), 3.89-4.00 (m, 2H), 3.67-3.74 (m, 1H), 3.28(s, 3H), 1.02 (d, 3H, J=8 Hz).

Example 3532-(7-(4-Chlorobenzyl)-3-methyl-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-methylacetamide

The title compound was prepared using the method of example 348 but withheating at 50° C. for 15 h. White solid: 0.18 g, 63% yield: LCMSretention time=4.084 minutes and 99% purity, LCMS MH⁺ 538. ¹H NMR(DMSO-d₆) δ 7.92-7.98 (m, NH), 7.60 (t, 1H, J=8 Hz), 7.47-7.51 (m, 1H),7.38-7.45 (m, 5H), 7.29-7.34 (d, 1H, J=8 Hz), 5.42 (s, 2H), 4.41 (s,2H), 3.28 (s, 3H), 2.57 (d, 3H, J=4 Hz).

Example 3547-(4-Chlorobenzyl)-3-methyl-1-(thiazol-5-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 348 but withheating at 50° C. for 3 h. White solid, 0.088 g, 29% yield: LCMSretention time=4.552 minutes and 99% purity, LCMS MH⁺ 564. ¹H NMR(DMSO-d₆) δ 8.97 (s, 1H), 7.85 (s, 1H), 7.58 (t, 1H, J=8 Hz), 7.46-7.48(m, 1H), 7.39-7.43 (m, 5H), 7.30 (d, 1H, J=12 Hz), 5.43 (s, 2H), 5.24(s, 2H), 3.29 (s, 3H).

Example 3557-(4-Chlorobenzyl)-1-(2-hydroxy-2-methylpentyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

7-(4-Chlorobenzyl)-3-methyl-1-(2-oxopropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.25 g, 0.48 mmol, example 348) was dissolved in THF (6 mL), cooled to0° C. and 2.0 M propyl magnesium bromide in THF (0.36 mL, 0.72 mmol) wasadded drop wise. The reaction was stirred in the cold for 15 min thenwarmed to room temperature and stirred 1 h. The reaction was dilutedwith water (100 mL) and extracted with ethyl acetate (3×75 mL). Thecombined extracts were dried with magnesium sulfate, filtered andevaporated under reduced pressure to a golden oil. The oil was purifiedusing a 25 g silica gel flash column eluted with 20% ethylacetate/hexanes to give7-(4-chlorobenzyl)-1-(2-hydroxy-2-methylpentyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.88 g, 32% yield) as a clear oil. LCMS retention time=4.792 minutesand 98% purity, LCMS MH⁺=567. ¹H NMR (DMSO-d₆) δ 7.59 (t, 1H, J=8 Hz),7.47-7.50 (m, 1H), 7.38-7.44 (m, 5H), 7.31 (d, 1H, J=8 Hz), 5.42 (s,2H), 4.23 (s, 1H) 3.92-4.02 (dd, 2H, J=4 Hz and 16 Hz), 3.29 (s, 3H),1.30-1.41 (m, 4H), 0.99 (s, 3H), 0.80 (t, 3H, J=8 Hz).

Example 3567-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

Step 17-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-2,6(3H,7H)-dione(3.73 g, 7.99 mmol, intermediate 9) and potassium carbonate (1.66 g,11.99 mmol) were combined in DMF (56 mL) and(3-bromopropoxy)(tert-butyl)dimethylsilane (2.43 g, 9.59 mmol) wasadded. The reaction was heated at 100° C. After heating for 3 h thereaction was cooled, diluted with water (200 mL) and extracted withethyl acetate (3×200 ml). The combined extracts were washed with 1Nlithium chloride (2×100 mL), dried with magnesium sulfate and evaporatedunder reduced pressure to provide1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(5.7 g crude) as a light golden oil. LCMS retention time=5.646 and 98%purity, LCMS MH⁺ 639.

Step 21-(3-((tert-Butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(5.7 g crude, 7.99 mmol) was dissolved in ethanol (40 mL) and 6N aqueousHCl (4 mL) was added. The clear solution was stirred at roomtemperature. After 1 h the reaction was evaporated under reducepressure, diluted with water (200 mL) and extracted with ethyl acetate(3×100 mL). The combined extracts were dried with magnesium sulfate,filtered and evaporated under reduced pressure to a clear oil. The oilwas purified using an 80 g silica gel flash column eluted with 1:1 ethylacetate/hexanes to provide7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(3.8 g, 90.9% yield) as a white crystalline solid. LCMS retentiontime=3.955 and 100% purity, LCMS MH⁺ 525. ¹H NMR (DMSO-d₆) δ 7.59 (t,1H, J=2 Hz), 7.47 (s, 1H), 7.41 (s, 4H), 7.41 (m, 1H), 7.31 (d, 1H, J=2Hz), 5.42 (s, 2H), 4.44 (t, OH, J=1 Hz), 3.92 (t, 2H, J=1 Hz), 3.41 (m,2H), 3.28 (s, 3H), 1.68 (m, 2H).

Example 3571-(3-Aminopropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dionehydrochloride

Step 17-(4-Chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(1.0 g, 2.14 mmol, intermediate 9),2-(3-bromopropyl)isoindoline-1,3-dione (0.63 g, 2.36 mmol), potassiumcarbonate (0.44 g, 3.21 mmol) and TBAI (0.040 g) were combined in DMF(20 mL) and heated at 100° C. for 3 h. The reaction was cooled to roomtemperature, diluted with water (200 mL) and extracted with ethylacetate (3×100 mL). The combined organic extracts were washed with 1Nlithium chloride (2×100 mL), dried with magnesium sulfate, filtered andthe solvent removed under reduced pressure to give a clear oil. The oilwas purified using an 80 g silica gel flash column eluted with agradient of 25% to 50% ethyl acetate/hexanes to give7-(4-chlorobenzyl)-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(1.4 g, 100% yield) as a white solid. LCMS retention time=4.660 minutesand 100% purity, LCMS MH⁺ 654. ¹H NMR (CDCl₃) δ 7.78-7.83 (m, 2H),7.65-7.70 (m, 2H), 7.41 (t, 1H, J=8 Hz), 7.32 (dd, 4H, J=12 Hz and 28Hz), 7.10-7.23 (m, 4H), 5.35 (s, 2H), 4.05-4.14 (m, 2H), 3.76 (t, 2H,J=8 Hz), 3.38 (s, 3H), 2.01-2.11 (m, 2H).

Step 27-(4-Chlorobenzyl)-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(1.4 g, 2.14 mmol) was slurried in ethanol (20 mL) and hydrazine hydrate(0.42 mL, 8.56 mmol) was added and the reaction was heated at reflux.The reaction at reflux changed to a clear solution then after 30 minsetup as a white mass. The reaction was cooled to room temperature,diluted with water (100 mL) and extracted with DCM (3×75 mL). Thecombined organic extracts were dried with magnesium sulfate, filteredand the solvent removed under reduced pressure to give an oil. The oilwas purified using a 40 g silica gel flash column eluted with 10%methanol/DCM to give a light tan solid. Solid was dissolved in DCM (5mL) and excess 1N HCl/diethyl ether was added. The solvent was removedunder reduced pressure to give1-(3-aminopropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dionehydrochloride (0.87 g, 49% yield) as a tan solid. LCMS retentiontime=2.802 minutes and 97% purity, LCMS MH⁺ 524. ¹H NMR (DMSO-d₆) δ7.91-8.11 (brd s, NH₂ and HCl), 7.60 (t, 1H, J=8 Hz), 7.38-7.48 (m, 6H),7.31 (d, 1H, J=12 Hz), 5.43 (s, 2H), 3.93 (t, 2H, J=8 Hz), 3.29 (s, 3H),2.73-2.85 (m, 2H), 1.83-1.94 (m, 2H).

Example 3581-(2-Aminoethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dionehydrochloride

The title compound was prepared using the method of example 357. Whitesolid, 0.062 g, 33% yield: LCMS retention time=2.802 minutes and 99%purity, LCMS MH⁺ 510. ¹H NMR (DMSO-d₆) δ 7.82-7.99 (brd s, NH₂ and HCl),7.62 (t, 1H, J=8 Hz), 7.38-7.48 (m, 6H), 7.31 (d, 1H, J=12 Hz), 5.43 (s,2H), 4.11 (m, 2H) 3.29 (s, 3H), 2.99-2.15 (m, 2H).

Example 359N-(3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl)acetamide

Notebook: C5-0249-047

1-(3-Aminopropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.10 g, 0.19 mmol, example 357) and TEA (0.80 mL, 0.57 mmol) werecombined in THF (1 mL). Acetyl chloride (0.28 mL, 0.42 mmol) was addedand the reaction was stirred at room temperature for 4 h. The reactionwas diluted with water (100 mL) and extracted with ethyl acetate (3×75mL). The combined extracts were dried with magnesium sulfate, filteredand evaporated under reduced pressure to an oil. The oil was purifiedusing a 2000 micron preparative TLC plate eluted with 5% methanol/DCM.Target band was scraped off plate and eluted off silica gel with eluentto giveN-(3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl)acetamide(0.053 g, 49% yield) as a light tan solid. LCMS retention time=3.789minutes and 99% purity, LCMS MH⁺ 566. ¹H NMR (DMSO-d₆) δ 7.78-7.82 (m,1H), 7.59 (t, 1H, J=8 Hz), 7.44-7.48 (m, 1H), 7.38-7.42 (m, 5H), 7.31(d, 1H, J=8 Hz), 5.42 (s, 2H), 3.87 (t, 2H, J=8 Hz), 3.28 (s, 3H), 2.04(dd, 2H, J=4 Hz and 12 Hz), 1.78 (s, 3H), 1.61-1.70 (m, 2H).

Example 360N-(3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl)methanesulfonamide

1-(3-Aminopropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.10 g, 0.19 mmol, example 357) and TEA (0.80 mL, 0.57 mmol) werecombined in THF (1 mL). Methanesulfonyl chloride (0.30 mL, 0.38 mmol)was added and the reaction was stirred at room temperature for 3 h. Thereaction was diluted with water (100 mL) and extracted with ethylacetate (3×75 mL). The combined extracts were dried with magnesiumsulfate, filtered and evaporated under reduced pressure to an oil. Theoil was purified using a 2000 micron preparative TLC plate eluted with5% methanol/DCM. Target band was scraped off plate and eluted off silicagel with eluent to giveN-(3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl)methanesulfonamide(0.045 g, 39% yield) as a tan solid. LCMS retention time=4.048 minutesand 99% purity, LCMS MH⁺ 602. ¹H NMR (DMSO-d₆) δ 7.59 (t, 1H, J=8 Hz),7.45-7.48 (m, 1H), 7.39-7.43 (m, 5H), 7.31 (d, 1H, J=8 Hz), 6.96 (t,1H), 5.43 (s, 2H), 3.91 (t, 2H, J=8 Hz), 3.29 (s, 3H), 2.96 (dd, 2H, J=4Hz and 12 Hz), 2.87 (s, 3H), 1.69-1.79 (m, 2H).

Example 3612-(7-(4-Chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)aceticacid

Step 17-(4-Chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(1.0 g, 2.14 mmol, intermediate 9), tert-butyl 2-bromoacetate (0.34 mL,2.36 mmol), and potassium carbonate (0.45 g, 3.21 mmol) were combined inDMF (20 mL) and heated at 50° C. for 2 h. The reaction was cooled toroom temperature diluted with water (200 mL) and extracted with ethylacetate (3×100 mL). The combined extracts were washed with 1N lithiumchloride (2×100 mL), dried with magnesium sulfate, filtered andevaporated under reduced pressure to givetert-butyl-2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate(1.24 g, 100% yield) as a clear oil. LCMS retention time=4.817 minutesand 97% purity, LCMS MH⁺ 581.

Step 2tert-Butyl-2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate(0.20 g, 0.34 mmol) was dissolved in DCM (4 mL) and TFA (0.26 ml, 3.4mmol) was added. The reaction was stirred at room temperature for 15 hthen evaporated under reduced pressure to give2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)aceticacid (0.18 g, 100% yield). LCMS retention time=3.915 minutes and 97%purity, LCMS MH⁺ 525. ¹H NMR (DMSO-d₆) δ 7.59 (t, 1H, J=8 Hz), 7.50-7.54(m, 1H), 7.45 (d, 1H, J=8 Hz), 7.41 (s, 4H), 7.31 (d, 1H, J=8 Hz), 5.41(s, 2H), 4.52 (s, 2H), 3.30 (s, 3H)

Example 3622-(7-(4-Chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-propylacetamide

2-(7-(4-Chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)aceticacid (0.25 g, 0.48 mmol, Example 361) and CDI (0.93 g, 0.57 mmol) werecombined in DMF (4 mL) and stirred at room temperature for 20 min.Propan-1-amine was added and the reaction was stirred at roomtemperature for 3 h. The reaction was diluted with water (100 mL) andextracted with ethyl acetate (3×75 mL). The combined extracts werewashed with 1N lithium chloride (2×75 mL), dried with magnesium sulfate,filtered and evaporated under reduced pressure to a white solid. Solidwas purified using a 25 g silica gel flash column eluted with 1%methanol/DCM to give2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-propylacetamide(0.13 g, 47% yield) as a white solid. LCMS retention time=4.070 min and99% purity, LCMS MH⁺ 566. ¹H NMR (DMSO-d₆) δ 7.99 (t, NH), 7.60 (t, 1H,J=8 Hz), 7.48-7.52 (m, 1H), 7.39-7.46 (m, 5H), 7.32 (d, 1H, J=8 Hz),5.42 (s, 2H), 4.42 (s, 2H), 3.31 (s, 3H), 3.00 (dd, 2H, J=8 Hz and 16Hz), 1.34-1.45 (m, 2H), 0.83 (t, 3H, J=8 Hz).

Example 3637-(4-Chlorobenzyl)-3-methyl-1-(2-oxobutyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 348. Whitesolid, 0.49 g, 85% yield: LCMS retention time=4.408 min and 99% purity,LCMS MH⁺ 537. ¹H NMR (DMSO-d₆) δ 7.60 (t, 1H, J=8 Hz), 7.51-7.54 (m,1H), 7.37-7.47 (m, 5H), 7.30-7.33 (m, 1H), 5.40 (s, 2H), 4.72 (s, 2H),3.28 (s, 3H), 2.55 (dd, 2H, J=8 Hz and 16 Hz), 0.96 (t, 3H, J=8 Hz).

Example 3647-(4-Chlorobenzyl)-8-ethoxy-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 1 Sodium (0.35 g, 15.03 mmol) was dissolved in ethanol (30 mL) and8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (1.63 g,3.01 mmol, intermediate 77) was added and the reaction was stirred atroom temperature for 24 h. The reaction was evaporated to dryness underreduced pressure, diluted with water (100 mL) and extracted with ethylacetate (3×75 mL). The combined extracts were dried with magnesiumsulfate, filtered and the solvent was removed under reduced pressure togive1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-ethoxy-3-methyl-1H-purine-2,6(3H,7H)-dione(1.5 g, 100% yield) as a light golden oil. LCMS retention time=5.317 minand 95% purity, LCMS MH⁺ 507.

Step 27-(4-Chlorobenzyl)-8-ethoxy-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

(1.5 g, 3.01 mmol) was dissolved in ethanol (20 mL) and 6N aqueous HCl(4 mL) was added. The clear solution was stirred at room temperature for1 h. The reaction was diluted with water (150 mL) and extracted with DCM(3×100 mL). The combined extracts were dried with magnesium sulfate,filtered and the solvent was removed under reduced pressure to anoff-white solid. The solid was purified using an 80 g silica gel flashcolumn eluted with 2% methanol/DCM which gave7-(4-chlorobenzyl)-8-ethoxy-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(1.0 g, 84% yield) as a white solid. LCMS retention time=3.173 min and98% purity, LCMS MH⁺ 393. ¹H NMR (DMSO-d₆) δ 7.35 (dd, 4H, J=4 Hz and 12Hz), 5.20 (s, 2H), 4.47 (dd, 2H, J=8 Hz and 16 Hz), 4.43 (t, 1H, J=4Hz)), 3.88 (t, 2H, J=8 Hz), 3.40 (dd, 2H, J=4 Hz and 12 Hz), 3.36 (s,3H), 1.62-1.71 (m, 2H), 1.33 (t, 3H, J=8 Hz).

Example 3657-(4-Chlorobenzyl)-1-(2-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

7-(4-Chlorobenzyl)-3-methyl-1-(2-oxobutyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.44 g, 0.82 mmol, example 363) was dissolved in methanol (8 mL) andDCM (1 mL), then cooled to 0° C. Sodium borohydride (0.93 g, 2.46 mmol)was added portion wise over 20 min and reaction was stirred in the coldfor 2 h. The reaction solvent was removed under reduced pressure thenthe mixture was diluted with water (100 mL) and extracted with ethylacetate (3×75 mL). The combined organic extracts were dried withmagnesium sulfate, filtered and the solvent removed under reducedpressure to give a clear oil. The oil was purified using an 40 g silicagel flash column eluted with 1% methanol/DCM to give7-(4-chlorobenzyl)-1-(2-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(0.32 g, 73% yield) as a white solid. LCMS retention time=4.265 min and97% purity, LCMS MH⁺ 539. ¹H NMR (DMSO-d₆) δ 7.59 (t, 1H, J=8 Hz),7.45-7.48 (m, 1H), 7.38-7.45 (m, 5H), 7.30 (d, 1H, J=12 Hz), 5.43 (s,2H), 4.56 (d, 1H, J=4 Hz), 3.92-4.00 (m, 1H), 3.65-3.76 (m, 2H), 3.28(s, 3H), 1.23-1.41 (m, 2H).

Example 3667-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(propylamino)-1H-purine-2,6(3H,7H)-dionehydrochloride

Step 18-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.25 g, 0.46 mmol, intermediate 77) and propan-1-amine (1.44 mL, 9.2mmol) were combined in ethanol (5 mL) and heated at reflux for 24 h. Thereaction was cooled to room temperature, diluted with water (75 mL) andextracted with ethyl acetate (3×75 mL). The combined organic extractswere dried with magnesium sulfate, filtered and the solvent evaporatedunder reduced pressure to yield a light golden oil. The oil was purifiedusing a 25 g silica gel column eluted with 20% ethyl acetate/hexanes togive1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-(4-chlorobenzyl)-3-methyl-8-(propylamino)-1H-purine-2,6(3H,7H)-dione(0.15 g, 63% yield) as a white solid. LCMS retention time=5.013 min and97% purity, LCMS MH⁺ 520.

Step 21-(3-((tert-Butyldimethylsilyl)oxy)propyl-7-(4-chlorobenzyl)-3-methyl-8-(propylamino)-1H-purine-2,6(3H,7H)-dione(0.15 g, 0.29 mmol) was dissolved in ethanol (3 mL) and 6N aqueous HCl(0.5 mL) was added. The clear solution was stirred at room temperaturefor 1 h. The reaction solvent was removed under reduced pressure to give7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(propylamino)-1H-purine-2,6(3H,7H)-dionehydrochloride (0.13 g, 100% yield) as a white foam. LCMS retentiontime=3.021 min and 99% purity, LCMS MH⁺ 406. ¹H NMR (DMSO-d₆) δ 7.31(dd, 4H, J=8 Hz and 42 Hz), 6.15-6.48 (brd s, NH₂ and HCl), 5.30 (s,2H), 3.84 (t, 2H, J=8 Hz), 3.38 (t, 2H, J=8 Hz), 3.34 (s, 3H), 3.26 (t,2H, J=8 Hz), 1.59-1.68 (m, 2H), 1.46-1.57 (m, 2H), 0.81 (s, 3H, J=8 Hz).

Example 3677-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-propoxy-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 364. Whitesolid, 0.14 g, 78% yield: LCMS retention time=2.914 min and 98% purity,LCMS MH⁺ 379. ¹H NMR (DMSO-d₆) δ 7.35 (dd, 4H, J=12 Hz and 40 Hz), 5.21(s, 2H), 4.36-4.44 (m, 3H), 3.89 (t, 2H, J=4 Hz), 3.41 (dd, 2H, J=4 Hzand 12 Hz), 3.35 (s, 3H), 1.62-1.78 (m, 4H), 0.88 (t, 3H, J=8 Hz).

Example 3687-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-8-methoxy-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 364. Whitesolid, 0.14 g, 78%: LCMS retention time=2.914 min and 98% purity, LCMSMH⁺ 379. ¹H NMR (DMSO-d₆) δ 7.34 (dd, 4H, J=8 Hz and 48 Hz), 5.21 (s,2H), 4.42 (t, 1H, J=4 Hz), 4.08 (s, 3H), 3.88 (t, 2H, J=8 Hz)),3.38-3.43 (m, 2H), 3.37 (s, 3H), 1.62-1.70 (m, 2H).

Example 3698-Butoxy-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 364. Whitesolid, 0.15 g, 77% yield: LCMS retention time=3.690 min and 97% purity,LCMS MH⁺ 421. ¹H NMR (DMSO-d₆) δ 7.34 (dd, 4H, J=4 Hz and 12 Hz), 5.21(s, 2H), 4.43 (m, 3H), 3.89 (t, 1H, J=8 Hz)), 3.41 (dd, 2H, J=4 Hz and12 Hz), 1.62-1.72 (m, 2H), 1.25-1.36 (m, 2H), 0.86 (t, 3H, J=8 Hz).

Example 3707-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-8-isopropoxy-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 364. Whitesolid, 0.056 g, 30% yield: LCMS retention time=3.355 min and 94% purity,LCMS MH⁺ 407. ¹H NMR (DMSO-d₆) δ 7.36 (dd, 4H, J=8 Hz and 48 Hz), 5.19(s, 2H), 5.12-5.18 (m, 1H), 4.44 (t, 1H, J=4 Hz), 3.80 (t, 2H, J=8 Hz),3.38-3.45 (m, 2H), 3.37 (s, 3H), 1.63-1.72 (m, 2H), 1.34 (d, 6H, J=8Hz).

Example 3717-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-morpholinoethoxy)-1H-purine-2,6(3H,7H)-dionehydrochloride

Step 1 Sodium (0.053 g, 2.31 mmol) was dissolved in 2-morpholinoethanol(5 mL) and8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.25 g, 0.46 mmol, intermediate 77) was added. The reaction was stirredat room temperature for 24 h. The reaction was diluted with water (75mL) and extracted with ethyl acetate (3×75 mL). The combined extractswere dried with magnesium sulfate, filtered and the solvent was removedunder reduced pressure to give1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-8-(2-morpholinoethoxy)-1H-purine-2,6(3H,7H)-dione(0.27 g, 100% yield) as a clear oil. LCMS retention time=2.990 min and96% purity, LCMS MH⁺ 592.

Step 21-(3-((tert-Butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-8-(2-morpholinoethoxy)-1H-purine-2,6(3H,7H)-dione(0.27 g, 0.46 mmol) was dissolved in ethanol (5 mL) and 6N aqueous HCl(1 mL) and stirred at room temperature for 1 h. The reaction wasevaporated and azeotroped with methanol (3×10 mL). The solid residue wastriturated with methanol (5 mL) and filtered. The white solid was washedwith diethyl ether (2×10 mL) and high vacuum dried to give7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-morpholinoethoxy)-1H-purine-2,6(3H,7H)-dionehydrochloride (0.14, 57% yield) as a white solid. LCMS retentiontime=1.908 min and 95% purity, LCMS MH⁺ 478. ¹H NMR (DMSO-d₆) δ 11.54(s, HCl), 7.38 (dd, 4H, J=12 and 28 Hz), 5.33 (2, 2H), 4.82-4.89 (m,2H), 3.75-3.95 (m, 2H), 3.58-3.64 (m, 2H), 3.33-3.44 (m, 5H), 3.06 (m,2H), 1.62-1.72 (m, 2H).

Example 3727-(4-Chlorobenzyl)-8-(2-(dimethylamino)ethoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dionehydrochloride

The title compound was prepared using the method of example 371. Whitesolid, 0.153 g, 95% yield: LCMS retention time=1.837 min and 94% purity,LCMS MH⁺ 436. ¹H NMR (DMSO-d₆) δ 10.70 (s, HCl), 7.37-7.42 (m, 4H), 5.35(s, 2H), 4.77-4.83 (m, 2H), 3.87-3.93 (m, 3H), 3.52-3.60 (m, 2H),3.40-3.44 (t, 2H, J=8 Hz), 3.39 (s, 3H), 2.50 (s, 6H), 1.62-1.72 (m,2H).

Example 3737-(4-chlorobenzyl)-8-(cyclopentyloxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 1 Cyclopentanol (0.21 mL, 2.31 mmol) was dissolved in THF (5 mL)and sodium hydride (60% in oil, 0.092 g, 2.31 mmol) was added. Thereaction was stirred for 1 h.8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.25 g, 0.46 mmol, intermediate 77) was added and the reaction wasstirred at room temperature for 15 h. The reaction was diluted withwater (100 mL) and extracted with ethyl acetate (3×75 mL). The combinedextracts were dried with magnesium sulfate, filtered and the solvent wasremoved under reduced pressure to give1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.25 g, 100% yield) as a golden oil. LCMS retention time=5.843 min and71% purity, LCMS MH⁺ 547.

Step 21-(3-((tert-Butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.25 g, 0.46 mmol) was dissolved in ethanol (5 mL) and 6N aqueous HCl(1 mL) was added. The clear solution was stirred at room temperature for1 h. The reaction was diluted with water (100 mL) and extracted withethyl acetate (3×100 mL). The combined extracts were dried withmagnesium sulfate, filtered and the solvent was removed under reducedpressure to a golden oil. The oil was purified using a 2000 micronpreparative TLC plate eluted with ethyl acetate. Target band was scrapedoff plate, eluted off silica gel with ethyl acetate and evaporated underreduced pressure to give7-(4-chlorobenzyl)-8-(cyclopentyloxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.028 g, 14% yield) as a white solid. LCMS retention time=3.656 min and98% purity, LCMS MH⁺433. ¹H NMR (DMSO-d₆) δ 7.34 (dd, 4H, J=12 and 48Hz), 5.34-5.40 (m, 1H), 5.18 (s, 2H), 4.42 (t, 1H, J=4 Hz), 3.89 (t, 2H,J=8 Hz), 3.38-3.45 (m, 2H), 3.36 (s, 3H), 1.55-1.93 (m, 8H).

Example 3747-(4-Chlorobenzyl)-8-(cyclohexyloxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 373. Whitesolid, 0.86 g, 42% yield: LCMS retention time=3.929 min and 97% purity,LCMS MH⁺ 447. ¹H NMR (DMSO-d₆) δ 7.35 (dd, 4H, J=12 Hz and 36 Hz), 5.20(s, 2H), 4.92-4.99 (m, 1H), 4.42 (t, 1H, J=4 Hz), 3.99 (t, 2H, J=8 Hz),3.38-3.44 (m, 2H), 3.35 (s, 3H), 1.83-1.94 (m, 2H), 1.50-1.72 (m, 6H),1.20-1.45 (m, 4H).

Example 3757-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(pentyloxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 373. Whitesolid, 0.13 g, 63% yield: LCMS retention time=3.886 min and 98% purity,LCMS MH⁺ 435. ¹H NMR (DMSO-d₆) δ 7.34 (dd, 4H, J=8 Hz and 44 Hz), 5.21(s, 2H), 4.36-4.49 (m, 3H), 3.99 (t, 3H, J=8 Hz), 3.37-3.45 (m, 2H),3.35 (s, 3H), 1.62-1.72 (m, 4H), 1.16-1.30 (m, 4H), 0.82 (t, 3H, J=8Hz).

Example 3767-(4-Chlorobenzyl)-8-(cyclopentylmethoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

using the method of example 373. White solid, 0.13 g, 63% yield: LCMSretention time=3.970 min and 95% purity, LCMS MH⁺ 447 and. ¹H NMR(DMSO-d₆) δ 7.34 (dd, 4H, J=8 Hz and 44 Hz), 5.21 (s, 2H), 4.42 (brd s,1H), 4.31 (d, 2H, J=4 Hz), 3.89 (t, 3H, J=8 Hz), 3.41 (t, 2H, J=8 Hz),3.35 (s, 3H), 2.23-2.35 (m, 2H), 1.62-1.72 (m, 4H), 1.44-1.59 (m, 4H),1.16-1.28 (m, 2H).

Example 3777-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-((6-methylpyridin-3-yl)methoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 373. Whitesolid, 0.0.87 g, 44% yield: LCMS retention time=2.255 min and 97%purity, LCMS MH⁺ 470. ¹H NMR (DMSO-d₆) δ 7.34 (dd, 4H, J=8 Hz and 44Hz), 5.21 (s, 2H), 4.36-4.49 (m, 3H), 3.99 (t, 3H, J=8 Hz), 3.37-3.45(m, 2H), 3.35 (s, 3H), 1.62-1.72 (m, 4H), 1.16-1.30 (m, 4H), 0.82 (t,3H, J=8 Hz).

Example 378 Ethyl2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)acetate

Step 1 Diethyl malonate (0.35 mL, 2.31 mmol) was dissolved in DMF (5 mL)and sodium hydride (60% in oil, 0.74 g, 1.85 mmol) was added portionwise. The mixture was stirred for 15 min and8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.50 g, 0.92 mmol, intermediate 77) was added. The reaction was heatedat 100° C. for 15 h. The reaction was cooled, diluted with water (100mL) and extracted with ethyl acetate (3×75 mL). The combined extractswere washed with 1N lithium chloride (2×100 mL), dried with magnesiumsulfate, filtered and the solvent was removed under reduced pressure toa golden oil. The oil was purified using a 25 g silica gel flash columneluted with 20% ethyl acetate/hexanes to givediethyl-2-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)malonate(0.23 g, 40% yield) as a clear oil. LCMS retention time=5.015 min and95% purity, LCMS MH⁺ 621. ¹H NMR (DMSO-d₆) δ 7.27 (dd, 4H, J=8 Hz and 72Hz), 5.62 (d, 2H, J=12 Hz), 5.54 (s, 2H), 5.61 (s, 1H), 3.90-4.03 (m,6H), 3.62 (t, 2H, J=8 Hz), 3.37 (s, 3H), 1.70-1.78 (m, 2H), 1.08 (t, 6H,J=8 Hz), 0.80 (s, 9H).

Step 2Diethyl-2-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-trifluoromethyl)phenyl)malonate(0.23 g, 0.36 mmol) was slurried in 18% aqueous HCl (3 mL) and heated atreflux for 3 h, yielding a clear solution. The solvent was removed underreduced pressure and the residue was high vacuum dried for 15 h to give2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)aceticacid (0.14 g, 100% yield) as a tan solid. LCMS retention time=2.318 minand 70% purity, LCMS MH⁺ 407.

Step 3 Crude2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)aceticacid (0.14 g, 0.36 mmol) was dissolved in ethanol (5 mL) andconcentrated sulfuric acid (1 drop). The reaction was heated at refluxfor 1 h. The reaction was cooled, evaporated under reduced pressure toremove the ethanol then diluted with water (50 mL) and extracted withethyl acetate (3×40 mL). The combined extracts were dried with magnesiumsulfate, filtered and the solvent was removed under reduced pressure toa light golden oil. The oil was purified using a 12 g silica gel flashcolumn and eluted with 20% ethyl acetate/hexanes to give ethyl2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)acetate(0.062, 40% yield) as a light tan solid. LCMS retention time=2.804 minand 99% purity, LCMS MH⁺ 435. ¹H NMR (CDCl₃) δ 7.21 (dd, 4H, J=8 Hz and84 Hz), 5.57 (s, 2H), 4.11-4.23 (m, 4H), 3.77 (s, 2H), 3.59 (s, 3H),3.50-3.56 (m, 2H), 3.32-3.39 (m, 1H), 1.86-1.94 (m, 2H), 1.25 (t, 3H,J=8 Hz).

Example 3797-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione

Step 1 Sodium hydride (60% in oil, 0.15 g, 3.69 mmol) was added portionwise to ethyl-2-(3-(trifluoromethoxy)phenyl)acetate (1.03 g, 4.15 mmol)in DMF (5 mL) and the dark golden solution was stirred at roomtemperature for 20 min.8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.50 g, 0.92 mmol, intermediate 77) was added and the reaction washeated at 100° C. for 2 h. The reaction was cooled, diluted with water(100 mL) and extracted with ethyl acetate (3×100 mL). The combinedextracts were washed with 1N lithium chloride (2×100 mL), dried withmagnesium sulfate, filtered and the solvent was removed under reducedpressure to a golden oil. The oil was purified using a 40 g silica gelflash column eluted with 10% ethyl acetate/hexanes to giveethyl-2-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-trifluoromethoxy)phenyl)acetate(0.54 g, 82% yield) as a light golden oil. LCMS retention time=5.407 minand 99% purity, LCMS MH⁺ 709.

Step 2Ethyl-2-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-trifluoromethoxy)phenyl)acetatewas slurried in 6N HCl (6 mL) and heated at reflux for 1 h. The reactionsolution was cooled, diluted with water (50 mL) and extracted with DCM(3×50 mL). The combined extracts were dried with magnesium sulfate,filtered and the solvent was removed under reduced pressure to a lightgolden oil. The oil was purified using a 12 g silica gel flash columneluted with a gradient of 20% ethyl acetate/hexanes to 100% ethylacetate to give7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (0.088 g, 60% yield) as a clear oil. LCMS retention time=3.623min and 98% purity, LCMS MH⁺ 523. ¹H NMR (DMSO-d₆) δ 7.33 (t, 1H, J=8Hz), 7.25-7.29 (m, 2H), 7.05-7.18 (m, 5H), 5.61 (s, 2H), 4.41 (t, 1H,J=4 Hz), 4.24 (s, 2H), 3.89 (t, 2H, J=12 Hz), 3.40 (s, 3H), 3.38-3.43(m, 2H), 1.62-1.72 (m, 2H).

Example 380Ethyl-2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-trifluoromethoxy)phenyl)propanoate

Sodium (0.025 g, 1.07 mmol) was dissolved in ethanol (3 mL) andethyl-2-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-trifluoromethoxy)phenyl)acetate(0.33 g, 0.47 mmol, example 379, step 1) was added. The reaction wasstirred for 10 min and methyl iodide (0.29 mL, 4.7 mmol) and thereaction was heated at reflux for 1 h. The reaction was cooled,evaporated under reduced pressure, diluted with water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined extracts were driedwith magnesium sulfate, filtered and the solvent was removed underreduced pressure to a golden oil. The oil was purified using a 25 gsilica gel flash column eluted with 20% ethyl acetate/hexanes to giveethyl-2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-trifluoromethoxy)phenyl)propanoate(0.17 g, 67% yield) as a white foam. LCMS retention time=3.263 min and99% purity, LCMS MH⁺ 609. ¹H NMR (CDCl₃) δ 7.06-7.24 (m, 5H), 6.73 (d,2H, J=8 Hz), 5.14 (s, 2H), 4.39 (t, 1H, J=8 Hz), 3.95-4.05 (m, 2H),3.81-3.89 (m, 2H), 3.35-3.42 (m, 2H), 1.95 (s, 3H), 1.59-1.67 (m, 2H),1.09 (t, 3H, J=8 Hz).

Example 3817-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethyl)benzyl)-1H-purine-2,6(3H,7H)-dione

Step 1Ethyl-2-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-trifluoromethyl)phenyl)acetatewas prepared from intermediate 77 and ethyl3-trifluoromethylphenylacetate using the method of example 378, step 1.(0.45 g, 70% yield) as a yellow foam. LCMS retention time=5.334 min and87% purity, LCMS MH⁺ 693.

Step 27-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethyl)benzyl)-1H-purine-2,6(3H,7H)-dionewas prepared using the method of example 379, step 2. Clear oil, 0.032g, 44% yield: LCMS retention time=3.523 min and 99% pure, LCMS MH⁺ 507.¹H NMR (DMSO-d₆) δ 7.65-7.75 (m, 1H), 7.47-7.52 (m, 1H), 7.43 (d, 1H,J=4 Hz), 7.38 (s, 1H), 7.17 (dd, 4H, J=8 Hz and 68 Hz), 5.53 (s, 2H),4.29 (s, 2H), 4.11-4.15 (m, 1H), 3.90 (t, 1H, J=4 Hz), 3.40 (s, 3H),3.37-3.45 (m, 2H), 1.60-1.71 (m, 2H).

Example 382 Ethyl2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-(trifluoromethyl)phenyl)acetate

Ethyl-2-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-trifluoromethyl)phenyl)acetate(0.050 g, 0.72 mmol, example 381, step 1) was dissolved in ethanol (3mL) and 6N aqueous HCl (0.3 mL) was added.

The clear solution was stirred at room temperature for 1 h. The reactionsolvent was removed under reduced pressure, added DCM (3 mL) anddirectly spotted on a 2000 micron preparative TLC plate which was elutedwith 50% ethyl acetate/hexanes. Target band was scraped off plate,eluted off silica gel with ethyl acetate and the solvent removed underreduced pressure to give ethyl2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-(trifluoromethyl)phenyl)acetate(0.025 g, 50% yield) as a white foam. LCMS retention time=3.731 min and96% purity, LCMS MH⁺ 579. ¹H NMR (DMSO-d₆) δ 7.55-7.65 (m, 3H), 7.48 (t,1H, J=8 Hz), 7.12 (dd, 4H, J=8 Hz and 72 Hz), 5.69 (dd, 2H, J=16 Hz and32 Hz), 4.40 (brd s, 1H), 4.05 (dd, 2H, J=8 Hz and 16 Hz), 3.88 (t, 2H,J=8 Hz), 3.41 (s, 3H), 1.61-1.69 (m, 2H).

Example 383 Ethyl2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-(trifluoromethyl)phenyl)propanoate

Ethyl2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-(trifluoromethyl)phenyl)propanoatewas prepared from example 381, step 1 using the method of example 380.Pale yellow foam, 0.13 g, 61% yield: LCMS retention time=3.999 min and96% purity, LCMS MH⁺ 593. ¹H NMR (DMSO-d₆) δ 7.51 (s, 2H), 7.40 (t, 1H,J=8 Hz), 7.32 (d, 1H, J=8 Hz), 6.90 (dd, 4H, J=8 Hz and 92 Hz), 5.15 (s,2H), 4.39 (t, 1H), 3.98-4.07 (m, 2H), 3.84-3.95 (m, 3H), 3.48 (s, 3H),3.35-3.42 (m, 2H), 3.61 (s, 3H), 1.59-1.78 (m, 2H), 1.12 (t, 3H, J=8Hz).

Example 3842-(7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-(trifluoromethoxy)phenyl)acetonitrile

Step 1 Sodium hydride (60% in oil, 0.15 g, 3.69 mmol) was added portionwise to 2-(3-(trifluoromethoxy)phenyl)acetonitrile (0.84 g, 4.15 mmol)and stirred at room temperature over 15 min.8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.50 g, 0.92 mmol, intermediate 77) was added and the reaction wasstirred at room temperature for 1 h. The reaction was diluted with water(100 mL) and extracted with ethyl acetate (3×100 mL). The combinedextracts were washed with 1N lithium chloride (2×75 mL), dried withmagnesium sulfate, filtered and the solvent was removed under reducedpressure to a golden oil. The oil was purified using a 25 g silica gelflash column eluted with 10% ethyl acetate/hexanes to give2-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-trifluoromethoxy)phenyl)acetonitrile(0.58 g, 95% yield) as a pale yellow foam. LCMS retention time=5.265 minand 90% purity, LCMS MH⁺ 662.

Step 22-(1-(3-((tert-Butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-trifluoromethoxy)phenyl)acetonitrile(0.20 g, 0.30 mmol) was dissolved in ethanol (5 mL) and 6 N aqueous HCl(1 mL) was added. The clear solution was stirred at room temperature for1 h. The reaction was diluted with water (50 mL) and extracted with DCM(3×50 ml). The combined extracts were dried with magnesium sulfate,filtered and the solvent was removed under reduced pressure to yield agolden oil. The oil was purified using a 25 g silica gel flash columneluted with a gradient of 20% to 50% ethyl acetate/hexanes to give2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-(trifluoromethoxy)phenyl)acetonitrile(0.082 g, 50% yield) as a white foam. LCMS retention time=3.709 min and97% purity, LCMS MH⁺ 548. ¹H NMR (CDCl₃) δ 7.34 (t, 1H, J=8 Hz),7.05-7.25 (m, 5H), 6.88 (d, 2H, J=8 Hz), 5.54 (dd, 2H, J=12 Hz and 80Hz), 4.18 (t, 2H, J=8 Hz). 3.64 (s, 3H), 3.50-3.58 (m, 2H), 3.13 (t, 1H,J=8 Hz), 1.85-1.93 (m, 2H).

Example 3857-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(1-(3-trifluoromethoxy)phenyl)ethyl-1H-purine-2,6(3H,7H)-dione

Ethyl-2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-trifluoromethoxy)phenyl)propanoate(0.14 g, 0.23 mmol, example 380) was slurried in 6N HCl (6 mL) andheated at reflux for 15 h. The clear solution was cooled, diluted withwater (75 mL) and extracted with DCM (3×50 mL). The combined extractswere dried with magnesium sulfate, filtered and the solvent was removedunder reduced pressure to a clear oil. The oil was purified using a 2000micron preparative TLC plate eluted with 50% ethyl acetate/hexanes.Target band was collected and extracted with ethyl acetate. The extractswere evaporated under reduced pressure to give7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(1-(3-trifluoromethoxy)phenyl)ethyl-1H-purine-2,6(3H,7H)-dione(0.026 g, 22% yield) as a white foam. LCMS retention time=4.029 min and96% purity, LCMS MH⁺ 537. ¹H NMR (CDCl₃) δ 7.20-7.30 (m, 3H), 7.09 (d,1H, J=8 Hz), 7.00-7.05 (m, 2H), 6.91 (d, 2H, J=12 Hz), 5.38 (dd, 2H,J=16 Hz and 100 Hz), 4.18 (t, 2H, J=8 Hz), 4.00-4.09 (m, 1H), 3.67 (s,3H), 3.48-3.53 (m, 2H), 3.39 (t, 1H, J=4 Hz), 1.85-1.93 (m, 2H), 1.66(d, 3H, J=8 Hz).

Example 3867-(4-Chlorobenzyl)-8-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Ethyl2-)1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-trifluoromethoxy)phenyl)acetate(0.25 g, 0.352 mmol, example 379, step 1) was dissolved in THF (4 mL)and sodium borohydride (0.080 g, 2.11 mmol) was added. The reaction wasrefluxed for 15 min then methanol (2 mL) was added dropwise throughcondenser. After refluxing another 15 min the reaction was cooled andacidified with 6N HCl until pH 1 was achieved. The mixture was stirredat room temperature for 1 h. The reaction was diluted with water (100mL) and extracted with DCM (3×75 ml). The combined extracts were driedwith magnesium sulfate, filtered and the solvent was removed underreduced pressure to yield an oil. The oil was purified using a 25 gsilica gel column eluted with a gradient of 5% to 10% methanol/DCM togive7-(4-chlorobenzyl)-8-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.030 g, 13% yield) as a white foam. LCMS retention time=2.665 min and98% purity, LCMS MH⁺ 553. ¹H NMR (CDCl₃) δ 7.25-7.30 (m, 2H), 7.03 (dd,4H, J=8 Hz and 91 Hz), 7.11 (d, 1H, J=8 Hz), 6.99-7.02 (m, 1H),5.26-5.57 (dd, 2H, J=16 Hz and 91 Hz), 5.30 (s, 1H), 4.17 (t, 2H, J=8Hz), 4.04-4.10 (m, OH), 3.67 (s, 3H), 3.46-3.50 (m, 3H), 3.20-3.27 (m,1H), 1.85-1.93 (m, 2H).

Example 3877-(4-Chlorobenzyl)-8-(1-hydroxyethyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 18-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.25 g, 0.46 mmol, intermediate 77) was dissolved in THF (5 mL) andcooled to

−78° C. To the clear solution was added 2.5 M n-butyllithium in hexanes(0.20 mL, 0.51 mmol) dropwise. The reaction was stirred in the cold for5 min and acetaldehyde (0.13 mL, 2.31 mmol) was added. The reaction waswarmed to room temperature and stirred for 1 h. The reaction was dilutedwith water (100 mL) and extracted with ethyl acetate (3×75 mL). Thecombined extracts were dried with magnesium sulfate, filtered and thesolvent was removed under reduced pressure to leave a golden oil. Theoil was purified using two 1000 microns preparative TLC plates elutedwith 50% ethyl acetate/hexanes. Target band was extracted with ethylacetate and the solvent was removed under reduced pressure to give1-(3-((tert-butyldimethysilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(1-hydroxyethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.052 g, 30% yield) as a clear oil. LCMS retention time=4.490 min and97% purity, LCMS MH⁺ 507.

Step 21-(3-((tert-butyldimethysilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(1-hydroxyethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.052 g, 0.10 mmoL) was dissolved in ethanol (2 mL) and 6N aqueous HCl(0.5 mL) was added. The clear solution was stirred at room temperaturefor 1 h. The reaction was diluted with water (25 mL) and extracted withDCM (3×25 mL). The combined organic extracts were dried with magnesiumsulfate, filtered and the solvent removed under reduced pressure to agolden oil. The oil was purified using a 2000 micron preparative TLCplate eluted with 50% ethyl acetate/hexanes. Target band was extractedwith ethyl acetate and the solvent was removed under reduced pressure togive7-(4-chlorobenzyl)-8-(1-hydroxyethyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.012 g, 29% yield) as a clear oil. LCMS retention time=2.429 min and96% purity, LCMS MH⁺ 393. ¹H NMR (CDCl₃) δ 7.25 (dd, 4H, J=8 Hz and 64Hz), 5.65 (dd, J=12 Hz and 40 Hz), 4.91-4.97 (m, 1H), 4.19 (t, 2H, J=4Hz), 3.61 (s, 3H), 3.51-3.55 (m, 2H), 2.52 (d, 1H, J=4 Hz), 1.87-1.93(m, 2H), 1.57 (d, 3H, J=4 Hz).

Example 3887-(4-Chlorobenzyl)-8-(1-hydroxy-2-methylpropyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 18-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.50 g, 0.923 mmol, intermediate 77) was dissolved in THF (5 mL) andcooled to −78° C. To the clear solution was slowly added drop wise 2.5 Mn-butyllithium in THF (0.35 mL, 0.877 mmol) followed by the immediateaddition of isobutyraldehyde (0.42 mL, 4.61 mmol). The reaction waswarmed to room temperature and stirred for I h. The reaction was dilutedwith water (75 mL) and extracted with ethyl acetate (3×75 mL). Thecombined extracts were dried with magnesium sulfate, filtered and thesolvent was removed under reduced pressure to yield an oil. The oil waspurified using a 25 g silica column eluted with a gradient of 10% to 30%ethyl acetate/hexanes yielding1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(1-hydroxy-2-methylpropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.20 g, 40% yield) as a light golden oil. LCMS retention time=4.923 minand 98% purity, LCMS MH⁺ 535.

Step 21-(3-((tert-Butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(1-hydroxy-2-methylpropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.19 g, 0.355 mmol) was dissolved in ethanol (5 mL) and 6 N HCl (0.5mL) was added. The clear solution was stirred at room temperature for 1h. The reaction was diluted with water (75 mL) and extracted with DCM(3×50 ml). The combined extracts were dried with magnesium sulfate,filtered and the solvent was removed under reduced pressure to yield awhite solid. Solid was slurried in diethyl ether (4 mL) and collected togive7-(4-chlorobenzyl)-8-(1-hydroxy-2-methylpropyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.085 g, 56% yield) as a white solid. LCMS retention time=3.263 min and94% purity, LCMS MH⁺ 421. ¹H NMR (CDCl₃) δ 7.23 (dd, 4H, J=8 Hz and 68Hz), 5.59 (dd, 2H, J=16 Hz and 40 Hz), 4.43 (t, 1H, J=8 Hz). 4.17 (t,2H, J=8 Hz), 3.59 (s, 3H), 3.48-3.54 (m, 2H), 3.35-3.40 (m, 1H), 2.48(d, 1H, J=8 Hz), 2.08-2.16 (m, 1H), 1.85-1.92 (m, 2H), 1.03 (d, 3H, J=8Hz), 0.82 (d, 3H, J=8 Hz).

Example 3897-(4-Chlorobenzyl)-8-(3-chlorophenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 18-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.50 g, 0.92 mmol, intermediate 77), potassium carbonate (0.255 g, 1.85mmol) and 3-chlorophenol (0.104 mL, 0.97 mmol) were combined in DMF (5mL) and heated at 90° C. for 3 h. The reaction was cooled to roomtemperature, diluted with water (100 mL) and extracted with ethylacetate (3×75 mL). The combined organic extracts were washed with 1Nlithium chloride (2×100 mL), dried with magnesium sulfate, andconcentrated under reduced pressure to yield a light golden oil (0.65g). The oil was purified using a 24 g silica gel column eluted with agradient of 10% to 20% ethyl acetate/hexanes to yield1-(3-(((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(3-chlorophenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dioneas an off-white solid (0.413 g, 76% yield). LCMS retention time=5.598min and 98% purity, LCMS MH⁺589.

Step 21-(3-(((tert-Butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(3-chlorophenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.413 g, 0.70 mmol) was dissolved in ethanol (8 mL) and 6N HCl (1 mL)was added. The clear solution was stirred at room temperature for 1 h.The reaction was diluted with water (75 mL) and extracted with DCM (3×75mL). The combined organic extracts were dried with magnesium sulfate,and concentrated under reduced pressure to leave an off-white solid. Thesolid was slurried in diethyl ether (3 mL) and filtered to yield7-(4-chlorobenzyl)-8-(3-chlorophenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.30 g, 90% yield) as an off-white solid. LCMS retention time=3.810 minand 99% purity, LCMS MH⁺ 475. ¹H NMR (DMSO-d₆) δ 7.15-7.41 (m, 8H), 5.41(s, 2H), 4.20 (t, 2H, J=8 Hz), 3.49-3.51 (m, 2H), 3.45 (s, 3H),1.87-1.93 (m, 2H).

The following examples 390a through 390r were prepared using the twostep method of example 389

Example 390a7-(4-Chlorobenzyl)-8-(3,4-dichlorophenoxy)l-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 0.34 g, 92% yield: LCMS retention time=4.080 min and 99%purity, LCMS MH⁺=509. ¹H NMR (CDCl₃) δ 7.50 (d, 1H, J=12 Hz), 7.31-7.44(m, 5H), 7.15 (dd, 2H, J=4 Hz and 8 Hz), 5.41 (s, 2H), 3.48-3.51 (m,2H), 3.45 (s, 3H), 1.87-1.95 (m, 2H).

Example 390b7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(m-tolyloxy)-1H-purine-2,6(3H,7H)-dione

White solid, 0.29 g, 76% yield: LCMS retention time=3.724 min and 96%purity, LCMS MH⁺=455. ¹H NMR (CDCl₃) δ (CDCl₃) δ 7.27-7.45 (m, 5H),7.01-7.13 (m, 3H), 5.41 (s, 2H), 4.20 (t, 2H, J=8 Hz), 3.49-3.57 (m,2H), 3.44 (s, 3H), 2.39 (s, 3H), 1.86-1.94 (m, 2H).

Example 390c7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-8-(3-methoxyphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 0.14 g, 41% yield: LCMS retention time=3.550 min and 97%purity, LCMS MH⁺=471. ¹H NMR (CDCl₃) δ (CDCl₃) δ 7.29-7.44 (m, 5H),6.79-6.86 (m, 3H), 5.41 (s, 2H), 4.20 (t, 2H, J=8 Hz), 3.82 (s, 3H),3.50-3.55 (m, 2H), 3.44 (s, 3H), 1.87-1.94 (m, 2H).

Example 390d7-(4-Chlorobenzyl)-8-(3-fluorophenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 0.23 g, 74% yield: LCMS retention time=3.584 min and 99%purity, LCMS MH⁺=459. ¹H NMR (CDCl₃) δ (CDCl₃) δ 7.30-7.43 (m, 5H),6.98-7.10 (m, 3H), 5.42 (s, 2H), 4.20 (t, 2H, J=8 Hz), 3.49-3.55 (m,2H), 3.45 (s, 3H), 1.88-1.93 (m, 2H).

Example 390e7-(4-Chlorobenzyl)-8-(4-chlorophenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 0.28 g, 76% yield: LCMS retention time=3.814 min and 99%purity, LCMS MH⁺=475. ¹H NMR (CDCl₃) δ 7.37-7.43 (m, 5H), 7.30-7.35 (m,2H), 7.19-7.23 (m, 2H), 5.41 (s, 2H), 4.20 (t, 2H, J=8 Hz), 3.47-3.56(m, 2H), 3.43 (s, 3H), 1.86-1.94 (m, 2H).

Example 390f7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(p-tolyloxy)-1H-purine-2,6(3H,7H)-dione

White solid, 0.14 g, 41% yield: LCMS retention time=3.732 min and 99%purity, LCMS MH⁺=455. ¹H NMR (CDCl₃) δ (CDCl₃) δ 7.46 (dd, 4H, J=8 Hzand J=44 Hz), 7.24 (dd, 4H, J=8 Hz and J=36 Hz), 5.41 (s, 2H), 4.19 (t,2H, J=8 Hz), 3.50-3.59 (m, 2H), 3.42 (s, 3H), 2.38 (s, 3H), 1.88-1.92(m, 2H).

Example 390g7-Benzyl-8-(3-chlorophenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 83 using the method ofexample 389. White solid, 0.11 g, 61% yield: LCMS retention time=3.503min and 98% purity, LCMS MH⁺=441. ¹H NMR (CDCl₃) δ 7.42-7.47 (m, 1H),7.31-7.38 (m, 5H), 7.24-7.30 (m, 2H), 7.14-7.18 (m, 1H), 5.45 (s, 2H),4.20 (t, 2H, J=8 Hz), 3.50-3.56 (m, 2H), 3.45 (s, 3H), 1.85-1.95 (m,2H).

Example 390h7-Benzyl-8-(3-fluorophenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 83 using the method ofexample 389. White solid, 0.17 g, 88% yield: LCMS retention time=3.282min and 98% purity, LCMS MH⁺=425. ¹H NMR (CDCl₃) δ 7.43-7.47 (m, 2H),7.30-7.41 (m, 4H), 7.04-7.08 (m, 2H), 6.96-7.02 (m, 1H), 5.45 (s, 2H),4.20 (t, 2H, J=8 Hz), 3.50-3.55 (m, 2H), 3.45 (s, 3H), 1.87-1.94 (m,2H).

Example 390i7-Benzyl-8-(4-chloro-3-fluorophenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 83 using the method ofexample 389. White solid, 0.25 g, 56% yield: LCMS retention time=3.860min and 99% purity, LCMS MH⁺=459. ¹H NMR (CDCl₃) δ 7.15-7.48 (m, 8H),5.46 (s, 2H), 4.20 (t, 2H, J=8 HZ), 3.50-3.61 (m, 3H), 3.43 (s, 3H),1.87-1.94 (m, 2H).

Example 390j7-Benzyl-1-(3-hydroxypropyl)-3-methyl-8-phenoxy-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 83 using the method ofexample 389. White solid, 0.18 g, 46% yield: LCMS retention time=3.435min and 99% purity, LCMS MH⁺=407. ¹H NMR (CDCl₃) δ 7.15-7.48 (m, 10H),5.46 (s, 2H), 4.20 (t, 2H, J=8 Hz), 3.50-3.61 (m, 3H), 3.43 (s, 3H),1.87-1.94 (m, 2H).

Example 390k7-Benzyl-8-(3-difluoromethoxy)phenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 83 using the method ofexample 389. White solid, 0.18 g, 39% yield: LCMS retention time=3.581min and 97% purity, LCMS MH⁺=473. ¹H NMR (CDCl₃) δ 7.31-7.47 (m, 6H),7.10-7.14 (m, 2H), 7.02-7.06 (m, 2H), 6.34-6.72 (t, 1H, J=18 Hz), 5.46(s, 2H), 4.20 (t, 2H, J=2 Hz). 3.51-3.55 (m, 2H), 3.45 (s, 3H),1.87-1.94 (m, 2H)

Example 390l7-(4-Chlorobenzyl)-8-(3-difluoromethoxy)phenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 0.14 g, 27% yield: LCMS retention time=3.820 min and 99%purity, LCMS MH⁺ 507. ¹H NMR (CDCl₃) δ 7.44 (s, 1H), 7.36 (dd, 4H, J=12Hz and 32 Hz), 7.11-7.14 (m, 2H), 7.04-7.07 (m, 1H), 6.54 (t, 1H, J=72Hz), 5.42 (s, 2H), 4.20 (t, 2H, J=2 Hz), 3.48-3.56 (m, 2H), 3.45 (s,3H), 1.87-1.94 (m, 2H).

Example 390m7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-phenoxy-1H-purine-2,6(3H,7H)-dione

White solid, 0.24 g, 59% yield: LCMS retention time=3.471 min and 99%purity, LCMS MH⁺=441. ¹H NMR (CDCl₃) δ 7.41-7.45 (m, 4H), 7.24-7.33 (m,4H), 5.42 (s, 3H), 4.20 (t, 2H, J=8 Hz), 3.51-3.54 (m, 2H), 3.43 (s,3H), 1.87-1.94 (m, 2H).

Example 390n3-((7-Benzyl-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)oxy)benzonitrile

The title compound was prepared from intermediate 83 using the method ofexample 389. White solid, 0.32 g, 74% yield: LCMS retention time=3.292min and 99% purity, LCMS MH⁺=466. ¹H NMR (CDCl₃) δ 7.52-7.65 (m, 4H),7.36 (dd, 4H, J=8 Hz and 24 Hz), 5.43 (s, 2H), 4.20 (t, 2H, J=8 Hz),3.51-3.56 (m, 2H), 3.45 (s, 3H), 1.88-1.93 (m, 2H).

Example 390o3-((7-Benzyl-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)oxy)benzonitrile

The title compound was prepared from intermediate 83 using the method ofexample 389. White solid, 0.24 g, 74%: LCMS retention time=3.581 min and99% purity, LCMS MH⁺=432. ¹H NMR (CDCl₃) δ 7.54 (s, 3H), 7.46 (d, 3H,J=8 Hz), 7.30-7.40 (m, 3H), 5.48 (s, 2H), 4.21 (t, 2H, J=8 Hz),3.50-3.56 (m, 2H), 3.45 (s, 3H), 1.88-1.96 (m, 2H)

Example 390p7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-8-(4-isopropylphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 0.33 g, 88% yield: LCMS retention time=4.160 min and 99%purity, LCMS MH⁺=483. ¹H NMR (CDCl₃) δ 7.38 (dd, 4H, J=8 Hz and 44 Hz),7.22 (dd, 4H, J=8 Hz and 40 Hz), 5.41 (s, 2H), 4.20 (t, 2H, J=8 Hz),3.50-3.59 (m, 2H), 3.45 (s, 3H), 2.91-2.98 (m, 2H), 1.85-1.95 (m, 2H),1.28 (d, 2H, J=2 Hz).

Example 390q7-Benzyl-1-(3-hydroxypropyl)-8-(4-isopropylphenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 83 using the method ofexample 389. White solid, 0.33 g, 91% yield: LCMS retention time=3.894min and 99% purity, LCMS MH⁺=449. ¹H NMR (CDCl₃) δ 7.48 (d, 2H, J=8 Hz),7.31-7.37 (m, 3H), 7.21 (dd, 4H, J=8 Hz and 32 Hz), 5.45 (s, 2H), 4.20(t, 2H, J=8 Hz), 3.62 (brd s, 1H), 3.50-3.56 (m, 2H), 3.44 (s, 3H),2.90-2.93 (m, 1H), 1.91 (m, 2H), 1.27 (d, 6H, J=2 Hz).

Example 390r7-Benzyl-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 83 using the method ofexample 389. White solid, 0.20 g, 79% yield: LCMS retention time=3.600min and 99% purity, LCMS MH⁺=475. ¹H NMR (CDCl₃) δ 7.34-7.59 (m, 8H),5.48 (s, 2H), 4.21 (t, 2H, J=8 Hz), 3.49-3.55 (m, 2H), 3.45 (s, 3H),1.88-1.95 (m, 2H)

Example 3917-Benzyl)-8-(4-fluoro-3-(trifluoromethyl)phenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 17-Benzyl-8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.50 g, 0.985 mmol, intermediate 83), potassium carbonate (0.272 g,1.97 mmol) and 4-fluoro-3-(trifluoromethyl)phenol (0.19 g, 1.03 mmol)were combined in DMF (5 mL). The reaction was heated at 90° C. After 6 hthe reaction was cooled, diluted with water (100 mL) and extracted withethyl acetate (3×75 mL). The combined extracts were dried with magnesiumsulfate, filtered and the solvent was removed under reduced pressure toyield a white solid. This solid was purified using a 25 g silica columneluted with 20% ethyl acetate/hexanes to give7-benzyl-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(4-fluoro-3-(trifluoromethyl)phenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.54 g, 90% yield) as a white solid. LCMS retention time=5.342 min and97% purity, LCMS MH⁺=607.

Step 27-Benzyl-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(4-fluoro-3-(trifluoromethyl)phenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.44 g, 0.686 mmol) was dissolved in ethanol (15 mL) and DCM (1 mL)then 6 N aqueous HCl (2.0 mL) were added. The clear solution was stirredat room temperature. After 1 h reaction was diluted with water (100 mL)and extracted with DCM (3×75 ml). The combined extracts were dried withmagnesium sulfate, filtered and the solvent was removed under reducedpressure to yield a white solid. Solid was slurried in diethyl ether (6mL) and filtered to give7-benzyl)-8-(4-fluoro-3-(trifluoromethyl)phenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.35 g, 79% yield) as a white solid. LCMS retention time=3.641 min and99% purity, LCMS MH⁺=493. ¹H NMR (CDCl₃) δ 7.23-7.52 (m, 8H), 5.47 (s,2H), 4.20 (t, 2H, J=8 Hz), 3.47-3.54 (m, 2H), 3.43 (s, 3H), 1.88-1.92(m, 2H).

Example 3927-(4-Chlorobenzyl)-8-(4-fluoro-3-(trifluoromethyl)phenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the two step method of example391. White solid, 0.33 g, 95% yield: LCMS retention time=3.870 min and99% purity, LCMS MH⁺=527. ¹H NMR (CDCl₃) δ 7.25-7.56 (m, 7H), 5.43 (s,2H), 4.20 (t, 2H, J=8 Hz), 3.55-3.51 (m, 2H), 3.45 (t, 2H, J=8 Hz), 3.43(s, 3H), 1.89-1.92 (m, 2H).

Example 3938-(4-Chloro-3-fluorophenoxy)-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the two step method of example 391except the crude product was purified by slurrying in ether andfiltration. White solid, 0.33 g, 95% yield: LCMS retention time=3.840min and 99% purity, LCMS MH⁺=493. ¹H NMR (CDCl₃) δ 7.45 (t, 1H, J=2 Hz),7.36 (dd, 4H, J=8 Hz and 24 Hz), 7.20 (dd, 1H, J=4 Hz and 12 Hz), 7.04(d, 1H, J=8 Hz), 5.41 (s, 2H), 4.20 (t, 2H, J=8 Hz), 3.51-3.55 (m, 2H),3.43-3.47 (m, 5H), 1.89-1.92 (m, 2H)

Example 3943-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanol

7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione(2.0 g, 3.81 mmol, example 356) and pyridinium chlorochromate (1.64 g,7.62 mmol) were dissolved in DCM (40 mL). The orange solution wasstirred at room temperature for 15 h. Solvent was decanted away fromsalts, absorbed onto silica gel and purified using a 40 g silica gelflash column eluted with 40% ethyl acetate/hexanes to give3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanol(1.25 g, 63% yield) as a white solid. ¹H NMR (CDCl₃) δ 9.84 (s, 1H),7.12-7.47 (m, 8H), 5.40 (s, 2H), 4.38 (t, 2H, J=8 Hz), 3.45 (s, 3H),2.75-2.83 (m, 2H).

Example 3957-Benzyl-8-ethoxy-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 1 Sodium metal (0.11 g, 4.93 mmol) was dissolved in ethanol (10 mL)and7-benzyl-8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.50 g, 0.985 mmol, intermediate 83) was added. The clear solution wasstirred at room temperature 15 h. The reaction was diluted with water(100 mL) and extracted with ethyl acetate (3×75 mL). The combinedextracts were dried with magnesium sulfate, filtered and the solvent wasremoved under reduced pressure to give7-benzyl-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-3-methyl-1H-purine-2,6(3H,7H)-dione(0.47 g, 100% yield) as a white solid. LCMS retention time=5.074 min and97% purity, LCMS MH⁺=473.

Step 27-Benzyl-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-3-methyl-1H-purine-2,6(3H,7H)-dione(0.47 g, 0.985 mmol) was dissolved in ethanol (8 mL) and 6 N HCl (2.0mL) was added. The clear solution was stirred at room temperature. After1 h the reaction was diluted with water (75 mL) and extracted with DCM(3×50 ml). The combined extracts were dried with magnesium sulfate,filtered and the solvent was removed under reduced pressure to yield awhite solid. Solid was slurried in hexanes (5 mL) and filtered to give7-benzyl-8-ethoxy-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.26 g, 73% yield) as a white solid. LCMS retention time=2.848 min and97% purity, LCMS MH⁺=359. ¹H NMR (CDCl₃) δ 7.26-7.40 (m, 5H), 5.26 (s,2H), 4.53-4.59 (m, 2H), 4.17 (t, 2H, J=8 Hz), 3.49-3.51 (m, 5H),1.85-1.91 (m, 2H), 1.45 (t, 3H, J=8 Hz).

Example 3967-Benzyl-1-(3-hydroxypropyl)-3-methyl-8-propoxy-1H-purine-2,6(3H,7H)-dione

The title product was prepared using the two step method of example 395.White solid, 0.32 g, 87% yield: LCMS retention time=3.119 min and 99%purity, LCMS MH⁺=373.

Example 397 tert-Butyl3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoate

7-(4-Chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)-1H-purine-2,6(3H,7H)-dione(0.50 g, 1.07 mmol, intermediate 9), tert-butyl 3-bromopropanoate (0.22mL, 1.29 mmol) and potassium carbonate (0.22 g, 1.61 mmol) were combinedin DMF (5 mL) and heated at 100° C. for 24 h. The reaction was cooled,diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL).The combined extracts were washed with 1N lithium chloride (2×50 mL),dried with magnesium sulfate, filtered and the solvent was removed underreduced pressure to leave a white solid. This solid was purified using a25 g silica gel flash column eluted with 10% ethyl acetate/hexanes togive tert-butyl3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoate(0.26 g, 41% yield) as a white solid. LCMS retention time=4.841 min and99% purity, LCMS MH⁺=595. ¹H NMR (CDCl₃) δ 7.12-7.46 (m, 8H), 5.41 (s,2H), 4.29 (t, 2H, J=8 Hz), 3.53 (s, 3H), 2.61 (t, 2H, J=8 Hz), 1.43 (s,9H).

Example 3983-(7-(4-Chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoicAcid

tert-Butyl3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoate(0.23 g, 0.383 mmol, Example 397) was dissolved in DCM (4 mL) and TFA(0.57 mL, 7.66 mmol) was added. The reaction was stirred at roomtemperature for 1 h; then the solvent was removed under reduced pressureto leave a golden oil (0.21 g). The oil was purified using a 12 g silicagel column eluted with 5% methanol/DCM to give3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoicacid (0.13 g, 63% yield) as an white solid. LCMS retention time=3.903min and 99% purity, LCMS MH⁺=539. ¹H NMR (CDCl₃) δ 7.14-7.47 (m, 8H),5.41 (s, 2H), 4.35 (t, 2H, J=8 HZ), 3.44 (s, 3H), 2.77 (t, 2H, J=8 HZ).

Example 3998-(3-Chlorophenoxy)-1-(3-hydroxypropyl)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 18-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione(0.50 g, 1.03 mmol, intermediate 82), 3-chlorophenol (0.14 g, 1.08mmol), potassium carbonate (0.29 g, 2.06 mmol) were combined in DMF (5mL) and heated at 90° C. for 15 h. The reaction was cooled, diluted withwater (100 mL) and extracted with ethyl acetate (3×75 mL). The combinedextracts were washed with 1 N LiCl (2×75 mL), dried with magnesiumsulfate, filtered and evaporated under reduced pressure to give1-(3-((tert-butyldimethylsilyl)oxy)propyl-8-(3-chlorophenoxy)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione(0.55 g, 100% yield) as a yellow oil. LCMS retention time=6.238 min and85% purity, LCMS MH⁺=535.

Step 21-(3-((tert-Butyldimethylsilyl)oxy)propyl-8-(3-chlorophenoxy)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione(0.55 g, 1.03 mmol) was dissolved in ethanol (10 mL) and 6N HCl (2 mL)was added and the reaction was stirred at room temperature for 1 h. Thereaction was diluted with water (100 mL) and extracted with DCM (3×75mL). The combined extracted were dried with magnesium sulfate, filteredand evaporated under reduced pressure to leave a golden oil. The oil waspurified using a 24 g silica gel flash column eluted with 50% ethylacetate/hexanes to give8-(3-chlorophenoxy)-1-(3-hydroxypropyl)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione(0.21 g, 49% yield) as a white solid. LCMS retention time=3.859 min and98% purity, LCMS MH⁺=421. ¹H NMR (CDCl₃) δ 7.35-7.38 (m, 2H), 7.24-7.28(m, 1H), 7.18-7.25 (m, 1H), 4.27 (t, 2H, J=8 Hz), 4.20 (t, 2H, J=8 Hz),3.52-3.58 (m, 3H), 3.47 (s, 3H), 1.86-1.94 (m, 2H), 1.70-1.78 (m, 2H),1.59-1.69 (m, 1H), 0.98 (d, 6H, J=8 Hz).

Example 4001-(3-Hydroxypropyl)-7-isopentyl-8-isopropoxy-3-methyl-1H-purine-2,6(3H,7H)-dione

Sodium (0.12 g, 5.15 mmol) was dissolved in isopropanol (8 mL) and8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione(0.50 g, 1.03 mmol, intermediate 82) was added. The reaction was stirredat room temperature for 15 h. The reaction was treated with 6N HCl toachieve pH=1, and stirred at room temperature for 1 h. The reaction wasdiluted with water (100 mL) and extracted with DCM (3×75 mL). Thecombined extracts were dried with magnesium sulfate, filtered andevaporated under reduced pressure to leave a golden oil. The oil waspurified using two 2000 micron preparative TLC plate eluted with 50%ethyl acetate/hexanes to give1-(3-hydroxypropyl)-7-isopentyl-8-isopropoxy3-methyl-1H-purine-2,6(3H,7H)-dione(0.27 g, 75 yield) as a white solid. LCMS retention time=3.325 min and97% purity, LCMS MH⁺=353. ¹H NMR (CDCl₃) δ 5.20-5.30 (m, 1H), 4.17 (t,2H, J=8 Hz), 4.07 (t, 2H, J=8 Hz), 3.73 (t, 1H, J=8 Hz), 3.45-3.54 (m,5H), 1.85-1.93 (m, 2H), 1.58-1.66 (m, 2H), 1.48-1.57 (m, 1H), 1.42 (d,6H, J=8 Hz), 0.94 (d, 6H, J=8 Hz).

Example 4018-Ethoxy-1-(3-hydroxypropyl)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 400 as awhite solid. LCMS retention time=3.050 min and 96% purity, LCMS MH⁺ 339.¹H NMR (CDCl₃) δ 4.53 (dd, 2H, J=8 Hz and 16 Hz), 4.17 (t, 2H, J=8 Hz),4.08 (t, 2H, J=8 Hz), 3.71 (t, 1H, J=4 Hz), 3.47-3.53 (m, 5H), 1.84-1.92(m, 2H), 1.60-1.67 (m, 2H), 1.49-1.58 (m, 1H), 1.45 (t, 2H, J=4 Hz),0.94 (d, 6H, J=4 Hz).

Example 4021-(3-Hydroxypropyl)-7-isopentyl-3-methyl-8-propoxy-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 400 as awhite solid. LCMS retention time=3.383 min and 95% purity, LCMS MH⁺=352.¹H NMR (CDCl₃) δ 4.42 (t, 2H, J=8 Hz), 4.17 (t, 2H, J=8 Hz), 4.09 (t,2H, J=8 Hz), 3.70 (t, 1H, J=4 Hz), 3.45-3.56 (m, 5H), 1.78-1.94 (m, 4H),1.51-1.72 (m, 3H), 1.04 (t, 3H, J=8 Hz), 0.94 (d, 6H, J=8 Hz).

Example 403 8-Butoxy1-(3-hydroxypropyl)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 400 as awhite solid. LCMS retention time=3.681 min and 99% purity, LCMS MH⁺=367.¹H NMR (CDCl₃) δ 4.47 (t, 2H, J=8 Hz), 4.16 (t, 2H, J=8 Hz), 4.08 (t,2H, J=8 Hz), 3.70 (t, 1H, J=8 Hz), 3.45-3.59 (m, 5H), 1.73-1.93 (m, 4H),0.99 (t, 3H, J=8 Hz), 0.94 (d, 6H, J=8 Hz).

Example 4047-Benzyl-8-(3,4-dichlorophenyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Step 17-Benzyl-8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.50 g, 0.985 mmol, intermediate 83), potassium carbonate (0.326 g,2.36 mmol), tetrakis(triphenylphosphine) palladium(0) (0.032 g, 0.028mmol) and 3,4-dichlorophenyl boronic acid (0.206 g, 1.08 mmol) werecombined in ethanol (12.0 mL), toluene (2.0 mL) and water (2.0 mL) in asealed vial. The reaction was heated at 85° C. for 18 h. The reactionwas cooled and filtered through Celite. The filtrate was diluted withwater (100 mL) and extracted with ethyl acetate (3×75 mL). The combinedextracts were dried with magnesium sulfate, filtered and the solvent wasremoved under reduced pressure to yield a golden solid. The solid waspurified using a 25 g silica gel CombiFlash column eluted with 20% ethylacetate/hexanes to give7-benzyl-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(3,4-dichlorophenyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.49 g, 86% yield) as a golden oil. LCMS retention time=5.489 min and97% purity, LCMS MH⁺=573.

Step 27-Benzyl-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(3,4-dichlorophenyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.49 g, 0.854 mmol) was dissolved in ethanol (15 mL) and 6 N HCl (2.0mL) was added. The clear solution was stirred at room temperature for 1h. The reaction was diluted with water (100 mL) and extracted with DCM(3×75 ml). The combined extracts were dried with magnesium sulfate,filtered and the solvent was removed under reduced pressure to give awhite solid. The solid was slurried in diethyl ether (5 mL) and filteredto give7-benzyl-8-(3,4-dichlorophenyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(0.28 g, 71% yield) as a white solid. LCMS retention time=3.567 min and96% purity, LCMS MH⁺=459. ¹H NMR (CDCl₃) δ 7.71 (s, 1H), 7.53 (d, 1H,J=8 Hz), 7.38-7.41 (d, 1H, J=4 Hz), 7.26-7.29 (m, 3H), 7.04 (d, 2H),5.64 (s, 2H), 4.20 (t, 2H, J=8 Hz), 3.65 (s, 3H), 3.47-3.54 (m, 2H),3.30 (t, 2H, J=8 Hz).

Example 4058-(3-Chlorophenyl)-1-(3-hydroxypropyl)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 82 using the method ofexample 404. Golden yellow solid, 0.31 g, 74% yield: LCMS retentiontime=3.516 min and 85% purity, LCMS MH⁺=405. ¹H NMR (CDCl₃) δ 7.65-7.70(m, 1H), 7.45-7.54 (m, 3H), 4.33-4.39 (m, 2H), 4.23 (t, 2H, J=4 Hz),3.63 (s, 3H), 3.52-3.58 (m, 2H), 3.43-3.48 (m, 2H), 1.89-1.96 (m, 2H),1.69-1.76 (m, 2H), 1.53-1.64 (m, 2H), 0.89 (d, 6H, J=4 Hz).

Example 4061-(3-Hydroxypropyl)-7-isopentyl-3-methyl-8-(3-(trifluoromethyl)phenyl)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 82 using the method ofexample 404. White solid, 0.089 g, 40% yield: LCMS retention time=3.598min and 97% purity, LCMS MH⁺=438.

Example 4071-(3-hydroxypropyl)-7-isopentyl-8-(2-isopropylphenyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

The title compound was prepared from intermediate 82 using the method ofexample 404. White solid, 0.089 g, 40% yield: LCMS retention time=3.749min and 99% purity, LCMS MH⁺=413.

Example 4088-(3-Fluorophenoxy)-1-(3-hydroxypropyl)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione

8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione(0.50 g, 1.03 mmol, intermediate 82), 3-fluorophenol (0.098 mL, 1.08mmol) and potassium carbonate (0.29 g, 2.06 mmol) were combined in DMF(8 mL) and heated at 90° C. for 15 h. The reaction was cooled to roomtemperature and acidified with 6N HCl to pH=1. The reaction was stirredfor 1 h then diluted with water (100 mL) and extracted with ethylacetate (3×75 mL). The combined extracts were washed with 1N LiCl (2×100mL), dried with magnesium sulfate, filtered and the solvent was removedunder reduced pressure to yield a golden oil. The oil was purified usinga 24 g silica gel flash column eluted with a gradient of 20% ethylacetate/hexanes to 100% ethyl acetate to give8-(3-fluorophenoxy)-1-(3-hydroxypropyl)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione(0.20 g, 48% yield) as a white solid. LCMS retention time=3.524 min and96% purity, LCMS MH⁺=405.

Example 4091-(3-Hydroxypropyl)-7-isopentyl-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

The title compound was prepared using the method of example 408. Whitesolid, 0.26 g, 55% yield: LCMS retention time=3.838 min and 99% purity,LCMS MH⁺=455.

The following examples 410a through 410w were prepared using the methodof example 404.

Example 410a7-Benzyl-8-(4-chloro-3-(trifluoromethyl)phenyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, LCMS retention time=3.625 min and 97% purity, LCMS MH⁺=493.¹H NMR (CDCl₃) δ 7.91 (s, 1H), 7.63 (d, 2H, J=8 Hz), 7.59 (d, 2H, J=8Hz), 7.30-7.35 (m, 2H), 7.01 (d, 2H, J=8 Hz), 5.55 (s, 2H), 4.21 (t, 2H,J=8 Hz), 3.66 (s, 3H), 3.47-3.55 (m, 2H), 3.28 (t, 2H, J=8 Hz),1.89-1.93 (m, 2H).

Example 410b7-Benzyl-8-(3-fluorophenyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 0.051 g, 80% yield: LCMS retention time=3.004 min and 99%purity, LCMS MH⁺=409.

Example 410c7-Benzyl-1-(3-hydroxypropyl)-3-methyl-8-(m-tolyl)-1H-purine-2,6(3H,7H)-dione

White solid, 0.054 g, 85% yield: LCMS retention time=3.133 min and 99%purity, LCMS MH⁺=405.

Example 410d7-benzyl-1-(3-hydroxypropyl)-8-(3-methoxyphenyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 0.051 g, 84% yield: LCMS retention time=2.950 min and 99%purity, LCMS MH⁺=421.

Example 410e7-Benzyl-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenyl)-1H-purine-2,6(3H,7H)-dione

White solid, 0.052 g, 80% yield: LCMS retention time=3.312 min and 99%purity, LCMS MH⁺=459.

Example 410f7-Benzyl-8-(4-chlorophenyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 0.050 g, 91% yield: LCMS retention time=3.227 min and 98%purity, LCMS MH⁺=425.

Example 410g7-Benzyl-8-(4-fluorophenyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 0.052 g, 60% yield: LCMS retention time=2.977 min and 99%purity, LCMS MH⁺=409.

Example 410h7-Benzyl-1-(3-hydroxypropyl)-3-methyl-8-(p-tolyl)-1H-purine-2,6(3H,7H)-dione

Clear oil, 0.028 g, 55% yield: LCMS retention time=3.122 min and 98%purity, LCMS MH⁺=405.

Example 410i7-Benzyl-1-(3-hydroxypropyl)-8-(4-methoxyphenyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 0.049 g, 91% yield: LCMS retention time=2.944 min and 96%purity, LCMS MH⁺=421.

Example 410j7-Benzyl-1-(3-hydroxypropyl)-3-methyl-8-(4-(trifluoromethyl)phenyl)-1H-purine-2,6(3H,7H)-dione

White solid, 0.052 g, 76% yield: LCMS retention time=3.348 min and 99%purity, LCMS MH⁺=459.

Example 410k7-Benzyl-8-(2-chlorophenyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Clear oil, 0.057 g, 93% yield: LCMS retention time=2.979 min and 99%purity, LCMS MH⁺=425.

Example 410l7-Benzyl-8-(2-fluorophenyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Golden oil, 0.030 g, 91% yield: LCMS retention time=2.858 min and 99%purity, LCMS MH⁺=409.

Example 410m7-Benzyl-1-(3-hydroxypropyl)-3-methyl-8-(o-tolyl)-1H-purine-2,6(3H,7H)-dione

White solid, 0.027 g, 77% yield: LCMS retention time=2.995 min and 98%purity, LCMS MH⁺=405.

Example 410n7-Benzyl-1-(3-hydroxypropyl)-8-(2-methoxyphenyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

White solid, 0.061 g, 86% yield: LCMS retention time=2.831 min and 98%purity, LCMS MH⁺=421.

Example 410o7-Benzyl-1-(3-hydroxypropyl)-3-methyl-8-(2-(trifluoromethyl)phenyl)-1H-purine-2,6(3H,7H)-dione

White solid, 0.017 g, 57% yield: LCMS retention time=3.055 min and 97%purity, LCMS MH⁺=459.

Example 410p7-Benzyl-1-(3-hydroxypropyl)-8-(4-(isopropylsulfonyl)phenyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Colorless oil, 0.057 g, 88% yield: LCMS retention time=2.886 min and 98%purity, LCMS MH⁺=498.

Example 410q7-Benzyl-1-(3-hydroxypropyl)-8-(2-isopropylphenyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Colorless oil, 0.038 g, 79% yield LCMS retention time=3.520 min, LCMSMH⁺=433 and 99% pure.

Example 410r7-Benzyl-1-(3-hydroxypropyl)-8-(3-isopropylphenyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Colorless oil, 0.026 g, 81% yield: LCMS retention time=3.609 min and 98%purity, LCMS MH⁺=433.

Example 410s8-([1,1′-Biphenyl]-3-yl)-7-benzyl-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Colorless oil, 0.045 g, 80% yield: LCMS retention time=3.609 min, LCMSMH⁺=467 and 99% pure.

Example 410t7-Benzyl-1-(3-hydroxypropyl)-3-methyl-8-(2-(trifluoromethoxy)phenyl)-1H-purine-2,6(3H,7H)-dione

Colorless oil, 0.048 g, 83% yield: LCMS retention time=3.231 min and 99%purity, LCMS MH⁺=475.

Example 410u7-Benzyl-8-(3-(difluoromethoxy)phenyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Colorless oil, 0.048 g, 83%: LCMS retention time=3.150 min and 99%purity, LCMS MH⁺=457.

Example 410v7-Benzyl-8-(4-(difluoromethoxy)phenyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Colorless oil, 0.050 g, 78% yield: LCMS retention time=3.161 min and 99%purity, LCMS MH⁺=457.

Example 410w7-Benzyl-8-(4-(difluoromethyl)phenyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

Colorless oil, 0.048 g, 75% yield: LCMS retention time=3.098 min and 99%purity, LCMS MH⁺=441.

Example 433 1-(5-Hydroxyhexyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione

Pentoxifylline (1.0 g, 3.59 mmol) was dissolved in methanol (20 mL) andDCM (3 mL) then cooled to 0° C. To the reaction was added sodiumborohydride (0.41 g, 10.8 mmol) portionwise over 30 min. The reactionwas stirred in the cold for 2 h; then it was evaporated to dryness underreduced pressure, diluted with water (100 mL) and extracted with ethylacetate (3×75 mL). The combined extracts were dried with magnesiumsulfate, filtered and the solvent was removed under reduced pressure togive 1-(5-hydroxyhexyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (0.72 g,71% yield) as a white solid. LCMS retention time=1.849 min and 98%purity, LCMS MH⁺ 281. ¹H NMR (DMSO-d₆) δ 8.00 (s, 1H), 4.31 (d, 1H, J=4Hz), 3.88 (s, 3H), 3.84 (t, 2H, J=8 Hz), 3.51-3.59 (m, 1H), 1.45-1.56(m, 2H), 1.25-1.37 (m, 4H), 1.02 (d, 3H, J=4 Hz).

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, are hereby incorporatedby reference in their entirety as if each individual publication orpatent was specifically and individually indicated to be incorporated byreference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

We claim:
 1. A method of treating a TRPC5 mediated disorder in asubject, the method comprising administering to the subject a compoundof the formula:

or a pharmaceutically acceptable salt thereof, to thereby treat thesubject; wherein the TRPC5 mediated disorder is post-traumatic stressdisorder.
 2. The method of claim 1, wherein the compound is of theformula:

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1,wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 5. The method of claim 1,wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 6. The method of claim 1,wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 7. A method of treating aTRPC5 mediated disorder in a subject, the method comprisingadministering to the subject a compound of the formula:

to thereby treat the subject; wherein the TRPC5 mediated disorder ispost-traumatic stress disorder.
 8. The method of claim 7, wherein thecompound is of the formula:


9. The method of claim 7, wherein the compound is of the formula:


10. The method of claim 7, wherein the compound is of the formula:


11. The method of claim 7, wherein the compound is of the formula:


12. The method of claim 7, wherein the compound is of the formula: